JP5612070B2 - Thienopyrimidinedione derivatives as TRPA1 modulators - Google Patents

Description

(Related application)
This application is filed on Mar. 23, 2009, India patent application No. 665 / MUM / 2009, filed Sep. 23, 2009, India patent application No. 2213 / MUM / 2009, filed Dec. 16, 2009. United States Patent Application No. 2906 / MUM / 2009; US Provisional Application No. 61 / 171,355 filed on April 21, 2009; US Provisional Application No. 61 / 251,994 filed on October 15, 2009 And claims the benefit of US Provisional Application No. 61 / 294,470, filed January 12, 2010, all of which are incorporated herein by reference.

  The present patent application relates to thienopyrimidinedione derivatives as TRPA1 modulators with transient receptor potential ankyrin 1 (TRPA1) activity.

  Transient receptor potential (TRP) channels or receptors are pain receptors. TRP channels are classified into seven subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPP (polycystin), TRPML (mucolipin), TRPA (ankyrin, ANKTM1), and TRPN (NOMPC) family. ing. The TRPC family can be classified into four subfamilies, (i) TRPC1, (ii) TRPC2, (iii) TRPC3, TRPC6, TRPC7, and (iv) TRPC4, TRPC5, based on functional similarity of the sequences. it can. There are currently six members in the TRPV family. TRPV5 and TRPV6 are more closely related to each other than TRPV1, TRPV2, TRPV3, or TRPV4. TRPA1 is most closely related to TRPV3 and more closely related to TRPV1 and TRPV2 than to TRPV5 and TRPV6. There are eight members in the TRPM family. Constituent members include: TRPM1 (Melastatin or LTRPC1), TRPM3 (KIAA1616 or LTRPC3), TRPM7 (TRP-PLIK, ChaK (1), LTRPC7), TRPM6 (ChaK2), TRPM2 ( TRPC7 or LTRPC2), TRPM8 (TRP-p8 or CMR1), TRPM5 (MTR1 or LTRPC5), and TRPM4 (FLJ20041 or LTRPC4). The TRPML family consists of mucolipin and includes TRPML1 (mucolipin 1), TRPML2 (mucolipin 2), and TRPML3 (mucolipin 3). The TRPP family consists of two groups: channels that are predicted to have 6 transmembrane domains and channels that have 11 transmembrane domains. TRPP2 (PKD2), TRPP3 (PKD2L1), and TRPP5 (PKD2L2) are all predicted to have a 6-transmembrane domain. TRPP1 (PKD1, PC1), PKD-REJ, and PKD-1L1 are all thought to have eleven transmembrane domains. The only member of the mammalian TRPA family is ANKTM1.

  TRPA1 is thought to be expressed in nociceptive neurons. Nociceptive neurons in the nervous system perceive peripheral damage and transmit pain signals. TRPA1 is bound to the membrane and is likely to act as a heterodimeric voltage-gated channel. It is considered that a large number of ankyrin repeats that have a specific secondary structure and are thought to form a spring-like structure are arranged at the N-terminus. TRPA1 is activated by various harmful stimuli including low temperature (activated at 17 ° C.), stimulating natural compounds (eg mustard, cinnamon, and garlic) and environmental stimuli (Non-Patent Document 1). . The harmful compound activates the TRPA1 ion channel through covalent modification of cysteine to form a covalent adduct. Various endogenous molecules produced during tissue inflammation / injury have been identified as pathological activators of the TRPA1 receptor. These include hydrogen peroxide produced by oxidative stress that occurs during inflammation, alkenyl aldehyde 4-HNE, a peroxidation product of intracellular lipids, and cyclopentenone prostaglandin produced from PGD2 during inflammatory / allergic reactions. Examples include gin 15dPGJ2. TRPA1 is also activated in a receptor-dependent manner by bradykinin (BK) released during tissue injury at the distal end.

  The difference between TRPA1 and other TRP receptors is that TRPA1 ligand binding persists for hours, thereby prolonging physiological responses (eg, pain) over time. Thus, effective antagonists are needed to dissociate electrophiles.

  Patent Documents 1 to 6 describe TRP channels as targets for the treatment of pain and related conditions.

International Publication No. 2009/158719 Pamphlet International Publication No. 2009/002933 Pamphlet International Publication No. 2008/0949099 Pamphlet International Publication No. 2007/073505 Pamphlet International Publication No. 2004/055504 Pamphlet International Publication No. 2005/089206 Pamphlet

MacPherson LJ et al, Nature, 2007, 445; 541-545.

  To find better analgesics to treat both acute and chronic pain and to develop treatments for various neuropathic and nociceptive pain conditions, diseases, symptoms, There is a need for more effective and safer treatments for and / or disorders.

The present invention relates to a compound of formula (I):
Or a pharmaceutically acceptable salt thereof (wherein
R ¹ and R ² may be the same or different and are independently hydrogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, (CR ^x R ^y ) _n OR ^x , COR ^x , COOR ^x , CONR ^x R ^y , (CH ₂ ) _n NR ^x R ^y , (CH ₂ ) _n CHR ^x R ^y , and (CH ₂ ) _n NHCOR ^x ;
R ³ is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl;
L _{^{is, - (CR x R y)}} n -, - O- (CR x R y) n -, - C (O) -, - NR x -, - S (O) m NR x -, - NR x _{^{(CR x R y) n -}} , and _{^{-S (O) m NR x (}} CR x R y) is a linker selected from _n;
Z ₁ and Z ₂ are independently sulfur or CR ^a ,
Provided that either Z ₁ or Z ₂ is always sulfur and the other is CR ^a ;
R ^a is hydrogen, cyano, halogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, OR ^x , (CR ^x R ^y ) _n OR ^x , COR ^x , COOR ^x , CONR ^{x _{R y, S (O) m}} NR x R y, NR x R y, NR x (CR x R y) n OR x, (CH 2) n NR x R y, (CH 2) n CHR x R y, _{^{NR x (CR x R y)}} n CONR x R y, (CH 2) n NHCOR x, (CH 2) n NH (CH 2) n SO 2 R x, (CH 2) n NHSO 2 R x, SR x , And OR ^x ;
U is substituted or unsubstituted aryl; thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyrazole, imidazole, furan, thiophene, pyrrole, 1,2,3-triazole, and 1,2,4- A substituted or unsubstituted 5-membered heterocyclic ring selected from the group consisting of triazoles; or selected from a substituted or unsubstituted 6-membered heterocyclic ring selected from the group consisting of pyrimidines, pyridines, and pyridazines;
V is hydrogen, cyano, nitro, —NR ^x R ^y , halogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, aryl, Arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclylalkyl, —C (O) OR ^x , —OR ^x , —C (O) NR ^x R ^y , —C (O) R ^x , and — Is selected from SO ₂ NR ^x R ^y ;
Alternatively, U and V together form an optionally substituted 3-7 membered saturated or unsaturated ring optionally containing one or more heteroatoms selected from O, S, and N. May be:
At each occurrence, R ^x and R ^y are independently hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, Selected from heteroarylalkyl, heterocycle, and heterocyclylalkyl;
At each occurrence, “m” and “n” are independently selected from 0 to 2).

According to one embodiment, the formula (Ia):
Or a pharmaceutically acceptable salt thereof, wherein:
R ¹ and R ² may be the same or different and are independently hydrogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, (CR ^x R ^y ) _n OR ^x , COR ^x , COOR ^x , CONR ^x R ^y , (CH ₂ ) _n NR ^x R ^y , (CH ₂ ) _n CHR ^x R ^y , and (CH ₂ ) _n NHCOR ^x ;
R ^a is hydrogen, cyano, halogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, OR ^x , (CR ^x R ^y ) _n OR ^x , COR ^x , COOR ^x , CONR ^{x _{R y, S (O) m}} NR x R y, NR x R y, NR x (CR x R y) n OR x, (CH 2) n NR x R y, (CH 2) n CHR x R y, _{^{NR x (CR x R y)}} n CONR x R y, (CH 2) n NHCOR x, (CH 2) n NH (CH 2) n SO 2 R x, (CH 2) n NHSO 2 R x, SR x , And OR ^x ;
U is substituted or unsubstituted aryl; thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyrazole, imidazole, furan, thiophene, pyrrole, 1,2,3-triazole, and 1,2,4- A substituted or unsubstituted 5-membered heterocyclic ring selected from the group consisting of triazoles; or selected from a substituted or unsubstituted 6-membered heterocyclic ring selected from the group consisting of pyrimidines, pyridines, and pyridazines;
V is hydrogen, cyano, nitro, —NR ^x R ^y , halogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, aryl, Arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclylalkyl, —C (O) OR ^x , —OR ^x , —C (O) NR ^x R ^y , —C (O) R ^x , and — Is selected from SO ₂ NR ^x R ^y ;
Alternatively, U and V together form an optionally substituted 3-7 membered saturated or unsaturated ring optionally containing one or more heteroatoms selected from O, S, and N. May be:
At each occurrence, R ^x and R ^y are independently hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, Selected from heteroarylalkyl, heterocycle, and heterocyclylalkyl;
At each occurrence, “m” and “n” are independently selected from 0 to 2).

  The following embodiments are illustrative of the present invention and are not intended to limit the scope of the claims to the specific embodiments illustrated.

According to one embodiment, specifically provided are compounds of formula (Ia), wherein R ^a is hydrogen or (C ₁ -C ₄ ) alkyl.

According to another embodiment, specifically provided are compounds of formula (Ia), wherein R ¹ and R ² are (C ₁ -C ₄ ) alkyl, preferably methyl.

  According to yet another embodiment, specifically represented by formula (Ia), wherein “U” is a substituted or unsubstituted 5-membered heterocycle, preferably thiazole, imidazole, isoxazole, pyrazole, or thiadiazole. A compound is provided.

  According to yet another embodiment, specifically provided are compounds of formula (Ia), wherein “U” is a substituted or unsubstituted 6-membered heterocycle, preferably pyrimidine.

According to yet another embodiment, specifically provided are compounds of formula (Ia), wherein “V” is substituted or unsubstituted aryl, preferably phenyl. In this embodiment, the substituents on phenyl may be one or more and are independently halogen (eg, F, Cl, or Br), cyano, alkyl (eg, t-butyl), haloalkyl (eg, , CF ₃ ), and haloalkoxy (eg, OCHF ₂ , OCF ₃ , OCH ₂ CF ₃ , or OCH ₂ CH ₂ CF ₃ ).

According to one embodiment, the formula (Ib):
Or a pharmaceutically acceptable salt thereof, wherein U, V, R ¹ , R ² , and R ^a are as defined above.

  The following embodiments are illustrative of the present invention and are not intended to limit the scope of the claims to the specific embodiments illustrated.

According to one embodiment, specifically provided is a compound of formula (Ib), wherein R ^a is hydrogen.

According to another embodiment, specifically provided is a compound of formula (Ib), wherein R ¹ and R ² are methyl.

  According to yet another embodiment, specifically provided are compounds of formula (Ib), wherein “U” is a substituted or unsubstituted 5-membered heterocycle, preferably thiazole.

According to yet another embodiment, specifically provided are compounds of formula (Ib), wherein “V” is substituted or unsubstituted aryl, preferably phenyl. In this embodiment, the substituents on phenyl may be one or more and are independently halogen (eg, F, Cl, or Br), alkyl (eg, CH ₂ CH (CH ₃ ) ₂ ), Selected from haloalkyl (eg, CF ₃ ) and haloalkoxy (eg, OCHF ₂ , OCF ₃ , or OCH ₂ CF ₃ ).

According to one embodiment, the formula (Ic):
Or a pharmaceutically acceptable salt thereof, wherein:
R ¹ , R ² , and R ^a may be the same or different and are each independently hydrogen or (C ₁ -C ₄ ) alkyl;
R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ may be the same or different and are each independently hydrogen, halogen, cyano, hydroxy, nitro, amino, substituted Or from the group consisting of unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocycle, and heterocyclylalkyl Selected).

  The following embodiments are illustrative of the present invention and are not intended to limit the scope of the claims to the specific embodiments illustrated.

According to one embodiment, specifically provided is a compound of formula (Ic), wherein R ¹ and R ² are methyl.

According to another embodiment, specifically, formula (Ic) wherein R ⁴ , R ⁵ , R ⁶ , and R ⁷ are independently selected from hydrogen, fluoro, trifluoromethyl, or trifluoromethoxy. Is provided.

According to yet another embodiment, specifically provided is a compound of formula (Ic), wherein R ⁸ is hydrogen.

According to yet another embodiment, specifically provided is a compound of formula (Ic), wherein R ⁹ is hydrogen.

According to one embodiment, the formula (Id):
Or a pharmaceutically acceptable salt thereof, wherein:
R ¹ , R ² , and R ^a may be the same or different and are each independently hydrogen or (C ₁ -C ₄ ) alkyl;
R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ may be the same or different and are each independently hydrogen, halogen, cyano, hydroxy, nitro, amino, substituted Or from the group consisting of unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocycle, and heterocyclylalkyl Selected).

  The following embodiments are illustrative of the present invention and are not intended to limit the scope of the claims to the specific embodiments illustrated.

According to one embodiment, specifically provided is a compound of formula (Id), wherein R ¹ and R ² are methyl.

According to another embodiment, specifically, formula (Id) wherein R ⁴ , R ⁵ , R ⁶ , and R ⁷ are independently selected from hydrogen, fluoro, trifluoromethyl, or trifluoromethoxy. Is provided.

According to yet another embodiment, specifically, the compound R ⁸ is represented by the formula (Id) is hydrogen is provided.

According to yet another embodiment, specifically, the compound R ⁹ is represented by formula (Id) is hydrogen is provided.

  The compounds of formula (I), (Ia), (Ib), (Ic), and (Id) are all structurally predictable from the chemical structures of the classes described herein. It should be understood to include stereoisomers, enantiomers, diastereomers, and pharmaceutically acceptable salts.

Formula (I), (Ia), (Ib), (Ic) having a human IC ₅₀ of less than 250 nM, preferably less than 100 nM, more preferably less than 50 nM with respect to TRPA1 activity, as measured by the methods described in this patent application. ) And (Id) are specifically contemplated.

  The reason why the compounds of the invention are used herein as TRPA1 modulators is that they are selective for one TRP isoform over other isoforms. For example, 2 times, 5 times, 10 times, more preferably at least 20 times, 40 times, 50 times than for one or more of TRPC6, TRPV5, TRPV6, TRPM8, TRPV1, TRPV2, TRPV4, and / or TRPV3 60 times, 70 times, 80 times, or at least 100 times, or even 1000 times, selective for TRPA1.

  According to another aspect, this patent application provides at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). And a pharmaceutical composition comprising: Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. The compounds described in this patent application may be combined with a pharmaceutically acceptable excipient (such as a carrier or diluent), diluted with a carrier, or a capsule, sachet, paper, or It may be enclosed in a carrier that may be in the form of another container.

  The compound of the present invention is administered as a pharmaceutical composition containing, for example, 0.1% to 99.5% (preferably 0.5% to 90%) of the active ingredient and a pharmaceutically acceptable carrier. can do. The maximum dosage will be determined by the condition being treated, the route of administration, the age, weight and condition of the patient and the discretion of the physician.

  The compounds of the invention can be used in the manufacture of a medicament for the treatment of the diseases described herein. The compounds and pharmaceutical compositions described herein are believed to be useful for modulation of the TRPA1 receptor and associated with various disease states.

  The compounds of the present invention can be administered alone or in combination with other therapeutic agents. For example, TRPA1 modulators are anti-inflammatory agents, anti-acne agents, anti-wrinkle agents, anti-scarring agents, anti-psoriatic agents, anti-proliferative agents, antibacterial agents, antiviral agents, antiseptics, anti-migraine agents, keratolysis Administered with one or more agents or hair growth inhibitors.

  According to another aspect, this patent application provides a subject in need thereof by administering to a subject an amount of one or more compounds described herein effective to cause inhibition of the TRPA1 receptor. Further provided is a method of inhibiting a TRPA1 receptor.

Definitions The term “halogen” or “halo” includes fluorine, chlorine, bromine, or iodine.

The term “alkyl” is a straight or branched hydrocarbon chain that consists solely of carbon and hydrogen atoms, does not contain unsaturation, contains 1 to 8 carbon atoms, and is joined to the rest of the molecule by a single bond. And refers to groups such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like. The term “C _1-6 alkyl” refers to an alkyl chain containing 1 to 6 carbon atoms. Unless otherwise specified, all alkyl groups described herein may be straight or branched and may or may not be substituted.

  The term “alkenyl” refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond and which may be straight or branched containing 2 to about 10 carbon atoms, for example And ethenyl, 1-propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like. Unless otherwise specified, all alkenyl groups described herein may be straight or branched and may or may not be substituted.

  The term “alkynyl” is a straight chain or branched chain containing at least one carbon-carbon triple bond and containing 2 to about 12 carbon atoms (preferably a group containing 2 to about 10 carbon atoms). Refers to a chain hydrocarbyl group, such as ethynyl, propynyl, butynyl and the like. Unless otherwise specified, all alkynyl groups described herein may be linear or branched and may or may not be substituted.

  The term “alkoxy” refers to a straight or branched chain saturated aliphatic hydrocarbon group bonded to an oxygen atom bonded to the core structure. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, 3-methylbutoxy and the like. Unless otherwise specified, all alkoxy groups described herein may be linear or branched and may or may not be substituted.

  The terms “haloalkyl” and “haloalkoxy” mean alkyl or alkoxy optionally substituted with one or more halogen atoms, where alkyl and alkoxy are as defined above. The term “halo” is used interchangeably herein with the term “halogen” and means F, Cl, Br, or I. Examples of “haloalkyl” include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl, 4,4,4-trifluorobutyl, 4,4-difluorocyclohexyl, Examples include, but are not limited to, chloromethyl, dichloromethyl, trichloromethyl, 1-bromoethyl and the like. Examples of “haloalkoxy” include fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy, pentachloroethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, 1-bromoethoxy However, it is not limited to these. Unless otherwise specified, all “haloalkyl” and “haloalkoxy” groups described herein may be linear or branched, unsubstituted or substituted. Also good.

  The term “cycloalkyl” means a non-aromatic mono- or polycyclic system containing 3 to about 12 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. Examples of polycyclic cycloalkyl groups include perhydronaphthyl, adamantyl, and norbornyl, bridged cyclic, or spiro bicyclic groups such as spiro (4,4) non-2-yl. However, it is not limited to these. Unless otherwise specified, all cycloalkyl groups described herein may or may not be substituted.

  The term “cycloalkylalkyl” refers to a ring-containing group containing from 3 to about 8 carbon atoms that is directly bonded to the alkyl group. Cycloalkylalkyl groups may be attached to the main structure at any carbon atom in the alkyl group that results in a stable structure. Non-limiting examples of cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylethyl, and cyclopentylethyl. Unless otherwise specified, all cycloalkylalkyl groups described herein may or may not be substituted.

The term “cycloalkylalkoxy” means alkoxy substituted with cycloalkyl, where “alkoxy” and “cycloalkyl” are as defined above (in either the broadest or preferred embodiments). It is. Examples of cycloalkylalkoxy groups include cyclopropylmethoxy, 1-cyclopropylethoxy, 2-cyclopropylethoxy, 1-cyclopropylpropoxy, 2-cyclopropylpropoxy, 3-cyclopropylpropoxy, 1-cyclopropyl-butoxy, 2-cyclopropyl-butoxy, 3-cyclopropyl-butoxy, 4-cyclopropyl-butoxy, cyclobutoxymethoxy, 1-cyclobutylethoxy, 2-cyclobutylethoxy, 1-cyclobutylpropoxy, 2-cyclobutylpropoxy, 3 -Cyclobutylpropoxy, 1-cyclobutylbutoxy, 2-cyclobutylbutoxy, 3-cyclobutylbutoxy, 4-cyclobutylbutoxy, cyclopentylmethoxy, 1-cyclopentylethoxy, 2-cyclopentyl ester 1-cyclopentylpropoxy, 2-cyclopentylpropoxy, 3-cyclopentylpropoxy, 1-cyclopentylbutoxy, 2-cyclopentylbutoxy, 3-cyclopentylbutoxy, 4-cyclopentylbutoxy, cyclohexylmethoxy, 1-cyclohexylethoxy, 2-cyclohexylethoxy, Examples include 1-cyclohexylpropoxy, 2-cyclohexylpropoxy, and 3-cyclohexylpropoxy. “Cycloalkylalkoxy” is preferably (C _3-6 ) cycloalkyl- (C _1-6 ) alkoxy. Unless otherwise specified, all cycloalkylalkoxy groups described herein may or may not be substituted.

  The term “cycloalkenyl” refers to a ring-containing group containing from 3 to about 8 carbon atoms containing at least one carbon-carbon double bond, such as cyclopropenyl, cyclobutenyl, cyclopentenyl, and the like. Unless otherwise specified, all cycloalkenyl groups described herein may or may not be substituted.

  The term “aryl” means a carbocyclic aromatic system containing one, two or three rings that may be fused. When the rings are fused, one of the rings must be fully unsaturated and the fused ring can be fully saturated or partially unsaturated. Or may be completely unsaturated. The term “fused” means that there is a second ring (ie, attached or formed) having (ie, sharing) two adjacent atoms in common with the first ring. . The term “fused” is synonymous with the term “condensed”. The term “aryl” includes aromatic groups such as phenyl, naphthyl, tetrahydronaphthyl, indane, and biphenyl. Unless otherwise specified, all aryl groups described herein may or may not be substituted.

The term “arylalkyl” refers to an aryl group as defined above directly bonded to an alkyl group as defined above, eg, —CH ₂ C ₆ H ₅ or —C ₂ H ₄ C ₆ H _5, etc. It is. Unless otherwise specified, all arylalkyl groups described herein may or may not be substituted.

  The term “heterocycle” refers to a stable 3-15 membered cyclic group consisting of a carbon atom and 1 to 5 heteroatoms selected from nitrogen, phosphorus, oxygen, and sulfur. For purposes of the present invention, a heterocyclic group may be a monocyclic, bicyclic, or tricyclic ring system, which may include fused, bridged, or spiro ring systems. Often, the nitrogen, phosphorus, carbon, oxygen, or sulfur atom in the heterocyclic group may optionally be oxidized to various oxidation states. Furthermore, the nitrogen atom may optionally be quaternized; the cyclic group may be partially or fully saturated (ie, heterocyclic or heteroaryl). Examples of such heterocyclic groups include azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl , Pyridyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, imidazolyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2 -Oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, Xazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, Quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl Sulfone, dioxaphosphoranyl, oxadiazolyl, chromanyl, isochromanyl, etc. It is below, but are not limited to these. The heterocyclic group may be attached to the main structure at any heteroatom or carbon atom that results in a stable structure. Unless otherwise specified, all heterocyclic groups described herein may or may not be substituted.

  The term “heterocyclyl” refers to a heterocyclic group as defined above. The heterocyclyl cyclic group may be attached to the main structure at any heteroatom or carbon atom that results in a stable structure. Unless otherwise specified, all heterocyclyl groups described herein may or may not be substituted.

  The term “heterocyclylalkyl” refers to a heterocyclic group bonded directly to an alkyl group. The heterocyclylalkyl group may be bonded to the main structure at any carbon atom in the alkyl group that results in a stable structure. Unless otherwise specified, all heterocyclylalkyl groups described herein may or may not be substituted.

  The term “heteroaryl” refers to an aromatic heterocyclic group. The heteroaryl cyclic group may be attached to the main structure at any heteroatom or carbon atom that results in a stable structure. Unless otherwise specified, all heteroaryl groups described herein may or may not be substituted.

  The term “heteroarylalkyl” refers to a heteroaryl cyclic group bonded directly to an alkyl group. The heteroarylalkyl group may be attached to the main structure at any carbon atom in the alkyl group that results in a stable structure. Unless otherwise specified, all heteroarylalkyl groups described herein may or may not be substituted.

Unless otherwise specified, the term “substituted” as used herein refers to substitution with any one or more of the following substituents or any combination: hydroxy, halogen, carboxyl, cyano, nitro, Oxo (= O), thio (= S), substituted or unsubstituted alkyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted haloalkoxy, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted Or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted Heteroaryl, substituted or unsubstituted heterocyclylalkyl ring, substituted or unsubstituted hete Arylalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted ^{guanidine, -COOR x ', -C (O} ) R x', -C (S) R x ', -C (O) NR x' R y ' ^{, -C (O) ONR x '} R y', -NR x 'CONR y' R z ', -N (R x') SOR y ', -N (R x') SO 2 R y ', - ( ^{= N-N (R x '} ) R y'), - NR x 'C (O) OR y', -NR x 'R y', -NR x 'C (O) R y', -NR x ' C (S) R ^{y ′} , —NR ^{x ′} C (S) NR ^{y ′} R ^{z ′} , —SONR ^{x ′} R ^{y ′} , —SO ₂ NR ^{x ′} R ^{y ′} , —OR ^{x ′} , —OR ^{x ′} C (O) NR ^{y ′} R ^{z ′} , —OR ^{x ′} C (O) OR ^{y ′} , —OC (O) R ^{x ′} , —OC (O) NR ^{x ′} R ^{y ′} , —R ^{x ′} NR ^{y 'C (O) R z'} , -R x 'OR y', -R x 'C (O) OR y' ^{-R x 'C (O) NR} y' R z ', -R x' C (O) R y ', -R x' OC (O) R y ', -SR x', -SOR x ', - SO ₂ R ^{x ′} , and —ONO ₂ (wherein R ^{x ′,} R ^{y ′} , and R ^{z ′} are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted Selected from substituted heteroaryl, substituted heterocyclylalkyl ring, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted heterocycle).

  The term “treatment” or “treating” of a condition, disorder, or symptom refers to (a) that the condition, disorder, or symptom may or may be susceptible to the condition, disorder, Or preventing or delaying the appearance of a clinical symptom of the condition, disorder, or symptom in a subject who has not experienced or shown clinical symptoms or symptoms of symptoms; (b) the condition; Inhibiting a disorder, or symptom, ie preventing or reducing the onset of a disease, or at least one clinical or latent symptom thereof; or (c) alleviating the disease, ie , Retreating at least one of the condition, disorder, or condition, or clinical or latent symptoms thereof.

  The term “subject” includes mammals (particularly humans) and other animals such as domestic animals (eg, pets including cats and dogs) and non-domestic animals (such as wild animals).

  “Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a condition, disorder, or symptom, is sufficient to effect such treatment. A “therapeutically effective amount” will vary depending on the compound, the disease and its severity, the age, weight, health and responsiveness of the subject being treated.

  The compounds described in this patent application may form salts. Non-limiting examples of pharmaceutically acceptable salts that form part of this patent application include salts derived from inorganic bases, salts of organic bases, salts of chiral bases, salts of natural amino acids, and non-naturally occurring salts. Examples include amino acid salts.

  Certain compounds of the present invention, including compounds of the formulas (I), (Ia), (Ib), (Ic), and (Id), are in stereoisomeric forms (eg, diastereomers and enantiomers). Body etc.). The present invention includes these stereoisomeric forms (eg, diastereomers and enantiomers) and mixtures thereof. Various stereoisomeric forms of the compounds of the present invention can be separated from each other by methods known in the art, or a given isomer can be obtained by stereospecific or asymmetric synthesis. . Also contemplated are tautomeric forms and mixtures of the compounds described herein.

Pharmaceutical Composition The pharmaceutical composition of the present patent application comprises at least one compound described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Including. Preferably, the pharmaceutical composition comprises an amount of a compound described herein in an amount sufficient to inhibit TRPA1 in a subject (eg, a human). The inhibitory activity of the compounds represented by formulas (I), (Ia), (Ib), (Ic), and (Id) can be measured by the assay described below.

  The compounds of the present invention may be combined with a pharmaceutically acceptable excipient (such as a carrier or diluent), diluted with a carrier, or in a capsule, sachet, paper, or other container. It may be enclosed in a carrier that may be in the form.

  The pharmaceutical composition can be prepared by techniques known in the art. For example, the active compound may be mixed with a carrier, diluted with a carrier, or enclosed in a carrier that may be in the form of an ampoule, capsule, sachet, paper, or other container. . Where the carrier functions as a diluent, the carrier may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or vehicle for the active compound. The active compound may be adsorbed in a granular solid container such as a sachet.

  The pharmaceutical composition may be in conventional forms such as capsules, tablets, aerosols, solutions, suspensions, or products for topical application.

Methods of Treatment The compounds and pharmaceutical compositions of the present invention can be administered to treat any disorder, symptom, or disease treatable by inhibition of TRPA1. For example, the compounds and pharmaceutical compositions of the invention are suitable for the treatment or prevention of the following diseases, symptoms and disorders mediated by or associated with the activity of the TRPA1 receptor: pain, chronic pain, complex topical Pain syndrome, neuropathic pain, postoperative pain, rheumatoid arthritis pain, osteoarthritis pain, back pain, visceral pain, cancer pain, hyperalgesia, neuralgia, migraine, neuropathy, chemotherapy-induced neuropathy, eye irritation , Bronchial irritation, skin irritation (atopic dermatitis), frostbite (cold), spasticity, tension disease, sclerosis, Parkinson's disease, diabetic neuropathy, sciatica, HIV-related neuropathy, postherpetic neuralgia, fibromyalgia, Nerve injury, ischemia, neurodegeneration, stroke, post-stroke pain, multiple sclerosis, respiratory disease, asthma, cough, COPD, inflammatory disorder, esophagitis, gastroesophageal reflux disease (GERD), hypertension Sex bowel syndrome, inflammatory bowel disease, pelvic hypersensitivity, urinary incontinence, cystitis, burns, psoriasis, eczema, emesis, stomach duodenal ulcer, and itching. The relationship between therapeutic effect and TRPA1 inhibition is described in, for example, Story G. et al. M.M. et al. Cell, 2003, 112, 819-829; McMahon S. et al. B. and Wood J. et al. N. , Cell, 2006, 124, 1123-1125; M.M. et al. Cell, 2006, 124, 1169-1181; Wissenbach, U, Nimeyer B .; A. and Flockerzi, V.M. Biology of the Cell, 2004, 96, 47-54 and references cited therein.

  Pain may be acute or chronic. Acute pain is usually within self-control, but chronic pain persists for 3 months or more and may significantly change the patient's personality, lifestyle, function, and overall QOL (K. M. Foley, Pain, in Cecil Textbook of Medicine; JC Bennett & F. Plum (eds.), 20th ed., 1996, 100-107). Pain perception may be triggered by any number of physical or chemical stimuli, and sensory neurons that mediate responses to this detrimental stimulus are also referred to as “nociceptors”. Nociceptors are primary sensory afferent (C fibers and Aδ fibers) neurons that are activated by a wide range of noxious stimuli including chemical, mechanical, thermal, and proton (pH <6) modalities. Nociceptors are nerves that perceive and respond to damaged body parts. Nociceptors convey tissue inflammation, imminent injury, or actual injury. When activated, nociceptors transmit pain signals to the brain (via peripheral nerves and spinal cord).

  Chronic pain can be classified as either nociceptive pain or neuropathic pain. Nociceptive pain includes inflammatory pain, such as tissue injury-induced pain and pain associated with arthritis. Neuropathic pain is caused by damage to sensory nerves in the peripheral or central nervous system and is maintained by abnormal somatosensory processing. Pain is typically very localized, constant, and often accompanied by dull, persistent or throbbing pain. Visceral pain is a type of nociceptive pain associated with internal organs. Visceral pain tends to be intermittent and not so localized. Nociceptive pain is usually transient, which means that pain typically recovers when tissue damage heals (arthritis is not transient) Is a notable exception).

General Methods of Preparation Described herein, including compounds of general formulas (I), (Ia), (Ib), (Ic), and (Id), as well as compounds described in specific examples The compounds to be prepared are prepared by techniques known to those skilled in the art using the reaction schemes and other methods described in Schemes 1-10. Furthermore, in the following synthesis schemes, when referring to specific acids, bases, reagents, coupling reagents, solvents, etc., other suitable acids, bases, reagents, coupling reagents, etc., may be used. It should be understood that it is within the scope of the invention. The compound obtained by using a general reaction scheme may have insufficient purity. These compounds can be purified by any of the methods for purifying organic compounds known to those skilled in the art, such as crystallization, silica gel chromatography, or alumina column chromatography, using, for example, various solvents in suitable ratios. it can. All possible stereoisomers are also contemplated as being within the scope of the present invention.

For synthesizing thienopyrimidinylacetamide represented by general formula (I), wherein Z ¹ , Z ² , R ¹ , R ² , R ³ , U, V, and L are as defined herein. A general approach is shown in Scheme 1. In a suitable solvent, the compound of formula (1) is converted to formula (2) in the presence of a suitable coupling agent such as 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide hydrochloride (EDCI) and a base. A compound of the formula (3) is obtained by a coupling reaction with an amine. Selective N-alkylation of a compound of formula (3) with a suitable alkylating agent of formula (4) in the presence of a base and a solvent provides a compound of general formula (I).

General for synthesizing thieno [2,3-d] pyrimidinylacetamide represented by the general formula (Ia ′), wherein R ¹ , R ² , U, and V are as defined herein. The approach is shown in Scheme 2. The synthesis starts with a commercially available 1,3-dialkylbarbituric acid of formula (5). According to known procedures (Singh, JS et al, Synthesis 1988, 342-344), intermediate (5) is formylated with POCl ₃ and DMF to give known 6-chloro-5-formyl. -1,3-dimethyluracil (6) is prepared. 6-Chloro-5-formyl-1,3-dialkyluracil (6) is treated with hydroxylamine in methanol and then dehydrated with phosphorus oxychloride to give 6-chloro-5-cyano-1 of formula (7). , 3-Dimethyluracil is obtained. Treatment of a compound of formula (7) with an alkyl mercaptoacetate of formula (8) (wherein R is alkyl) in the presence of a suitable base, provides a coupling reaction followed by in situ cyclization to give a compound of formula (9 To obtain an amino ester of This transformation is described in Motoi, Y. et al. et al, J. et al. Heterocyclic Chem. 1990, 717-721. It is the same as that described in. The amino ester (9) is diazotized and then subjected to halide substitution with copper halide (copper bromide or copper iodide) to obtain an intermediate of formula (10) (wherein X is a halogen). Reacting an aryl halide of formula (10) with an allylboronic acid pinacol ester of formula (11) in the presence of a palladium catalyst such as bis (triphenylphosphine) palladium dichloride or tetrakis (triphenylphosphine) palladium (0); An allyl derivative of formula (12) is obtained (for example, a procedure similar to the Suzuki-Miyaura Coupling described in Kotha, et al, Synlett 2005, 12, 1877-1890). Hydrolysis and decarboxylation of the allylthiophene derivative of formula (12) with copper in the presence of quinoline at high temperature yields an allylthienopyrimidinedione of formula (14) (Ludo., EJ. The procedure reported by Kennis. Et al in Biorg. & Med.Chem.Lett., 2000, 10, 71-74, and reported in Tetrahedron, 2005, 61, 3507-3513 by Mashraqui, SH et al. Procedure similar to the procedure). Under basic conditions, the compound of formula (14) is ozonolyzed in methanol, and the resulting ester (15) is hydrolyzed with an acidic aqueous solution to obtain the compound of formula (16) (this conversion is based on Mohler , D. L. et al, Synthesis, 2002, 745-748). A compound of general formula (Ia ′) is obtained by coupling a compound of formula (16) with an amine of formula (2) using standard amine coupling methods.

R ^a is an alkyl group (eg, methyl, ethyl, propyl, isopropyl), and R ¹ , R ² , U, and V are as defined above and the thieno [2,3- d] The approach to synthesize pyrimidinylacetamide is shown in Scheme 3. A functionalized thiophene of formula (18) is converted to a one-pot three-component coupling reaction (Gewald synthesis) using malononitrile, the appropriate aldehyde, and sulfur powder (Byrn, SR et al, J. Pharm, Sci., 2001, 90, 371). The compound of formula (18) is converted to the compound of formula (19) by performing a series of transformations well known in the art of organic synthesis. The compound of formula (19) was cyclized with triphosgene to obtain the compound of formula (20), and selective N-alkylation was performed to obtain the compound of formula (21). Halogenation of formula (21) (for example, N-bromosuccinimide or N-iodosuccinimide in the presence of BF ₃ -ether or trifluoromethanesulfonic acid) was performed to obtain a compound of formula (22). This transformation is described in George, O. et al. L. et al. Am. Chem. soc. 2004, 126, 15770-15776. A Suzuki-Miyaura coupling of an aryl halide of formula (22) and an allylboronic acid of formula (11) in the presence of Pd (0) results in the reaction of formula (23) as described in Scheme 1. Allylthiophene is obtained. Conversion of the compound of formula (23) to the compound of formula (24) can be carried out by methods known to those skilled in the art (see, for example, Postema, MHD et al, J. Org. Chem. 2003, 68, 4748-4754). The compound of formula (24) can be converted to the compound of formula (25) by oxidation methods well known in the literature. The compound of general formula (Ia) is obtained by coupling the compound of formula (25) with the amine of formula (2) using standard coupling methods.

A general approach for the synthesis of thieno [3,4-d] pyrimidinylacetamide of formula (Ib ′) where R ¹ , R ² , U, and V are as defined above is shown in Scheme 4. The known 6-methyluracil derivative (26) can be prepared by two different methods. In one approach, Egg, H. et al. N, N-dimethylurea is condensed with acetic anhydride in the presence of pyridine as reported by et al in Synthesis, 1982, 1071-1073. Alternatively, intermediate (26) can be obtained from Siberman, R .; B. et al. Am. Chem. Soc. 1982, 104, 6434-6439, and can be prepared by alkylation of 6-methyluracil. Friedel-Crafts acylation of intermediate (26) in the presence of a catalytic amount of a Lewis acid (eg, ZnCl ₂ ) provides a compound of formula (27). A similar procedure is described by Tsupak, E .; B. et al. Chemistry heterocyclic compounds, 2003, 39, 953-959. The compound of formula (27) was cyclized by Gewald synthesis and described by Tormyshey, V .; M.M. The desired 5-methylthieno [3,4-d] pyrimidinedione of formula (28) is obtained as described by et al in Synlett, 2006, 2559-2164. The compound of formula (28) is reacted with a dialkyl carbonate in the presence of a suitable base such as sodium hydride in a suitable solvent to give the diester of formula (29). Dealkoxycarbonylation of the compound of formula (29) with a suitable base such as sodium hydride or DMSO / NaCl / water provides the desired thieno [3,4-d] pyrimidine of formula (30). Dione ester was obtained. By conducting a coupling reaction of an ester of formula (30) with an appropriate amine of formula (2) using a suitable base such as sodium hydride in the presence of a suitable solvent such as anhydrous toluene or xylene. The compound represented by general formula (Ib ') was obtained.

Thieno [3,4-d] pyrimidinylacetamide represented by formula (Ib) , wherein R ^a is an alkyl group such as methyl, ethyl, propyl, and R ¹ , R ² , U, and V are as defined above Another approach for the synthesis of is shown in Scheme 5. The uracil derivative (26) prepared as described in Scheme 4 is treated with an alkyl halide of formula R ^a X in the presence of a suitable base such as lithium diisopropylamide to give a compound of formula (31). A similar approach is described by Hiriyakkanava, J. et al. et al., Tetrahedron Lett. 1992, 33 (41), 6173-6176. Friedel-Crafts acylation of the intermediate of formula (31) gives ketone (32). The compound of formula (32) is cyclized by the synthesis of Gewald to give the desired thieno [3,4-d] pyrimidinedione of formula (33). As described in Scheme 4, the compound of the formula (33) is reacted with a dialkyl carbonate in the presence of a strong base such as sodium hydride to carry out dealkoxycarbonylation to give a compound of the formula (34). Can be converted to an ester. By carrying out a coupling reaction of an ester of formula (34) with an appropriate amine of formula (2) using a suitable base such as sodium hydride in the presence of a suitable solvent such as anhydrous toluene or xylene. To obtain a compound represented by the general formula (Ib).

Another approach for the synthesis of thieno [3,4-d] pyrimidinylacetamide represented by formula (Ib ′) where R ¹ , R ² , U, and V are as defined above is shown in Scheme 6. Shirahashi, M .; The uracil derivative (26) was formylated using phosphorous oxychloride and anhydrous DMF as described in Yakugaku Zassi, 1971, 91, 1372 by et al to give the 5-formyl derivative of formula (35). The 5-formyl derivative (35) was treated with hydroxylamine hydrochloride and dehydrated with phosphorus oxychloride to obtain a 5-cyano derivative of the formula (36). A similar approach is described in Hirota, K .; et al., Heterocycle, 1998, 47, 871-882. The aminothiophene of formula (37) is obtained by reacting the intermediate of formula (36) with sulfur powder and morpholine under Gewald reaction conditions. The aminothiophene (37) is diazotized and substituted with a metal halide (copper bromide or copper iodide) to obtain a halide derivative of the formula (38). Aryl halide of formula (38) is converted to allylthiophene of formula (39) by Suzuki-Miyaura coupling reaction with allylboronic acid pinacol ester of formula (11) in the presence of Pd (0) catalyst. Can do. Allylthiophene of formula (39) can be converted to thieno [3,4-d] pyrimidinylacetic acid of formula (40) by oxidative cleavage of the terminal double bond as described in Scheme 1. A compound of general formula (Ib ′) is obtained by coupling the compound of formula (40) with the amine of formula (2) using standard coupling methods.

R ^a is hydrogen or alkyl, and R ¹ , R ² , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are as defined above in formula (Ic) or (Id) A general approach for the synthesis of the resulting compounds is shown in Scheme 7. A compound represented by general formula (Ic) is obtained by coupling a compound of formula (25) with an amine of formula (46) using a general amide coupling method.
Similarly, a compound represented by general formula (Id) is obtained by coupling a compound of formula (40) with an amine of formula (46) using a general amide coupling method.

Scheme 8 depicts a 2-amino-4-arylthiazole of formula (46) prepared from acetophenone of formula (45) using known approaches, wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are as defined above). Certain disubstituted and trisubstituted acetophenones were not commercially available and were prepared in three steps from the corresponding benzoic acid derivative of formula (41). That is, the acid of formula (41) was converted to the corresponding acid chloride of formula (42) using oxalyl chloride in anhydrous dichloromethane in the presence of a catalytic amount of DMF. Treatment with N, O-dimethylhydroxylamine hydrochloride of formula (43) in the presence of a suitable base such as triethylamine converts the acid chloride of formula (42) to the corresponding wine lebuamide of formula (44). Converted. Alkylmagnesium iodide was added to winelevamide of formula (44) to obtain an acetophenone derivative of formula (45).
Conversion of the acetophenone derivative of formula (45) to the 2-amino-4-substituted arylthiazole of formula (46) can be accomplished in two approaches as described in Scheme 8. In one case, acetophenone was converted to the corresponding phenacyl bromide and subsequently reacted with thiourea in a suitable solvent such as tetrahydrofuran under reflux conditions. The acetophenone derivative of formula (45) can also be converted in one step to 2-amino-4-arylthiazole (46) by reaction with thiourea and iodine in refluxing ethanol (Carroll, K. et al. , J. Am. Chem. Soc., 1950, 3722, and Naik, S. J .; Halkar, UP, ARKIVOC, 2005, xiii, 141-149).

Synthesis of 2-amino-4-arylimidazolamine of formula (48) wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ are as defined above, scheme 9 Shown in That is, the acetophenone derivative of formula (45) is reacted with bromine in acetic acid to obtain phenacyl bromide, which is reacted with acetylguanidine at reflux temperature in acetonitrile to obtain N-acetylimidazole of formula (47). N-deacetylation of (47) is carried out under acidic conditions to give 2-amino-4-arylimidazole of formula (48). This is described by Thomas, L .; et al. Org. Chem. 1994, 59, 7299-7305.

Some of the 5-amino-3-phenylpyrazoles used to synthesize the compounds of the present invention were commercially available. Commercially available 3-amino-1-arylpyrazole was prepared as shown in Scheme 10. The phenylhydrazine derivative of formula (49) is reacted with acrylonitrile in the presence of a suitable base such as sodium ethoxide or sodium methoxide in refluxing ethanol to give the dihydro derivative of the compound of formula (50). Duffin, G.M. F. et al, J. et al. Chem. Soc. , 1954, 408-415, and intermediate (50) is oxidized with N-bromosuccinimide to give a 3-amino-1-arylpyrazole derivative of formula (51) wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ are as defined above.

Experimental Unless otherwise stated, workup involves partitioning the reaction mixture into the organic and aqueous phases shown in parentheses, separating the layers, drying the organic layer with sodium sulfate, filtering, and evaporating the solvent. including. Purification unless otherwise stated generally involves purification by silica gel chromatography techniques using a polar ethyl acetate / petroleum ether mixture suitable as the mobile phase. The use of various eluent systems is shown in parentheses. The following abbreviations are used in the text: DMSO-d ₆ : hexadeuterodimethyl sulfoxide; DMAP: 4-dimethylaminopyridine; DMF: N, N-dimethylformamide; J: coupling constant in units of Hz; RT or rt: room temperature (22 ° C. to 26 ° C.); Aq. : Aqueous solution; AcOEt: ethyl acetate; equiv. Or eq. : Equivalent.

Intermediate Intermediate 1
(1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetic acid
Step 1 6-Chloro-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxaldehyde: Phosphorus oxychloride (690 mL) was added to anhydrous N, N-dimethylformamide (180 mL) ) At 0 ° C. The mixture was then warmed to room temperature. 1,3-Dimethylbarbituric acid (60 g, 384.27 mmol) was added in portions and refluxed for 45 minutes. Excess phosphorus oxychloride and DMF were distilled off under reduced pressure, and the viscous residue was poured into ice-cold water (2000 mL). The reaction mixture was brought to room temperature and extracted with chloroform (3 × 500 mL). The combined organic extracts were dried over Na ₂ SO ₄ and concentrated. The resulting crude product was then stirred in 10% ethyl acetate in hexane (150 mL) to give 58 g of product as a pale yellow solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ3. 41 (s, 3H), 3.69 (s, 3H), 10.18 (br s, 1H).

Step 2 6-Chloro-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxaldehyde oxime: Step 1 intermediate (56 g, 262.37 mmol) and hydroxylamine To a mixture of hydrochloride (22.8 g, 327.97 mmol) in methanol (525 mL), a solution of KOH (18.3 g, 327.97 mmol) in water (32 mL) was added over 1 hour while maintaining the reaction mixture below 10 ° C. Added. The mixture was stirred at room temperature for 1 hour and the resulting oxime precipitate was collected by filtration, washed with water (2 × 250 mL) and methanol (2 × 150 mL), and dried to give 46.3 g of product as a pale. Obtained as a yellow solid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.51 (s, 3H), 7.94 (s, 1H), 11.40 ( br s, 1H).

Step 3 6-Chloro-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile: Step 2 intermediate (46 g, 263.48 mmol) was converted to phosphorus oxychloride. (410 mL) was added in portions at room temperature and the reaction mixture was further stirred for 2 hours. Excess phosphorus oxychloride was evaporated under reduced pressure. The resulting crude residue was washed several times with diethyl ether and ground with water. The resulting solid was filtered, washed with methanol and dried to give 33.4 g of product as an off-white solid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.38 (s, 3H), 3.69 (s, 3H).

Step 4 Ethyl 5-amino-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carboxylate: Intermediate of Step 3 (32 g , 160.00 mmol), ethyl mercaptoacetate (19.4 mL, 176.88 mmol) and anhydrous sodium carbonate (17.0 g, 105.99 mmol) in ethanol (800 mL) was refluxed with stirring for 3 hours. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, washed with water, ethanol, and dried to give 41.6 g of product as an off-white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ1. 35 (t, J = 6.6 Hz, 3H), 3.39 (s, 3H), 3.49 (s, 3H), 4.29 (q, J = 6.9 Hz, 2H), 6. 83 (br s, 2H).

Step 5 Ethyl 5-bromo-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carboxylate: tert-butylnitrile (26. To a stirred solution of 3 mL, 220.21 mmol) in acetonitrile (590 mL), copper bromide (31.5 g, 220.21 mmol) was slowly added for 10-15 minutes. The intermediate from step 4 (41.4 g, 146.191 mmol) was added in portions at room temperature. The reaction mixture was heated at 65 ° C. for 3 hours. The mixture was cooled to room temperature, quenched with a saturated solution of sodium thiosulfate, 1N HCl (200 mL) was added and extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate and concentrated. The resulting crude product was purified by silica gel column chromatography using 3% ethyl acetate in chloroform to give 24.6 g of product as an off-white solid; ¹ H NMR (300 MHz, CDCl ₃ ) Δ 1.41 (t, J = 6.9 Hz, 3H), 3.42 (s, 3H), 3.57 (s, 3H), 4.39 (q, J = 6.9 Hz, 2H) ).

Step 6 Ethyl 5-allyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carboxylate: Intermediate of Step 5 (24 To a stirred solution of anhydrous THF (350 mL) in a nitrogen atmosphere was added cesium carbonate (46.0 g, 141.20 mmol) and allylboronic acid pinacol ester (23.8 ml, 127.08 mmol). The mixture was degassed for 10 minutes. Tetrakis (triphenylphosphine) palladium (0) (8.1 g, 7.06 mmol) was added and the reaction was refluxed for 24 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (250 mL) and extracted with ethyl acetate (3 × 100 mL). The combined extracts were concentrated and the resulting residue was purified by silica gel column chromatography using 5% ethyl acetate in petroleum ether to give 4.62 g of product as an off-white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.39 (t, J = 7.2 Hz, 3H), 3.41 (s, 3H), 3.56 (s, 3H), 4.18-4.24 ( m, 2H), 4.31-4.40 (m, 2H), 4.99-5.15 (m, 2H), 5.95-6.03 (m, 1H).

Step 7 5-Allyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidine-6-carboxylic acid: intermediate of Step 6 (4. To a stirred solution of 6 g, 14.93 mmol) in ethanol (50 mL) was added 1.25 M aqueous KOH (15.5 mL) and the mixture was refluxed for 2 hours. The solvent was concentrated under reduced pressure and acidified with 1N HCl. The separated solid was filtered and dried to give 3.50 g of product as an off-white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.42 (s, 3H), 3.56 ( s, 3H), 4.24 (d, J = 6.0 Hz, 2H), 5.01-5.18 (m, 2H), 5.95-6.05 (m, 1H).

Step 8 5-Allyl-1,3-dimethylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione: copper powder (231 mg, 3.642 g (atoms)), Step 7 Of intermediate (3.4 g, 12.142 mmol) in a quinoline (60 mL) suspension and the resulting mixture was stirred and heated under nitrogen for 3 hours at 235 ° C. The reaction mixture was cooled to room temperature, Diluted with ethyl acetate, washed with 1N HCl and water, the combined organic layers were dried and concentrated, and the crude product was purified by silica gel column chromatography by using 5% ethyl acetate in petroleum ether, 2.17 g of product was obtained as an off-white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.41 (s, 3H), 3.55 (s, 3H), 71 (s, 2H), 5.09-5.15 (m, 2H), 5.97-6.10 (m, 1H), 6.50 (s, 1H).

Step 9 Methyl (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetate: Intermediate of Step 8 (2.14 g , 9.033 mmol) in dichloromethane (106 mL) was added 2.5 M methanolic NaOH solution (60 mL). The solution was cooled (−78 ° C.) and bubbled with ozone gas for 90 minutes. The reaction mixture was warmed to room temperature, diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water, dried over Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel column chromatography using 5% ethyl acetate in petroleum ether to give 1.35 g of product as a pale yellow solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.39 (s, 3H), 3.47 (s, 3H), 3.74 (s, 3H), 3.95 (s, 2H), 6.70 (s, 1H).

Step 10 (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetic acid: intermediate of Step 9 (1.3 g, A mixture of 4.850 mmol) and 6N H ₂ SO ₄ (12 mL) in 1,4-dioxane (12 mL) was stirred at reflux for 1 hour to give a homogeneous pale yellow solution. The solution was cooled, diluted with water and extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with water, dried over Na ₂ SO ₄ and concentrated. The resulting residue was triturated in diethyl ether and the resulting solid was collected by filtration to give 450 mg of product as a white solid; ¹ H NMR (DMSO-d ₆ , 300 MHz) δ3. 21 (s, 3H), 3.45 (s, 3H), 3.79 (s, 2H), 7.01 (s, 1H), 12.22 (brs, 1H).

Intermediate 2
(1,3,6-Trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetic acid
Step 1 2-Amino-5-methylthiophene-3-carbonitrile: To a stirred solution of propionaldehyde (87.99 g, 1514 mmol) and sulfur powder (48.4 g, 1514 mmol) in anhydrous DMF (320 mL) was added triethylamine (127.7 mL). 909 mmol) was added dropwise at 0 ° C. The resulting dark solution was warmed to room temperature over 1 hour. A solution of malononitrile (100 g, 1514 mmol) in anhydrous DMF (180 mL) was transferred to the addition funnel and added dropwise. The resulting brown mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate ethyl acetate (3 × 500 mL). The combined organic extracts were washed with water (2 × 300 mL), dried over Na ₂ SO ₄ and concentrated. The resulting residue was purified by silica gel column chromatography using 10% ethyl acetate in petroleum ether to give 25.8 g of product as a light brown solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.28 (s, 3H), 4.60 (br. s, 2H), 6.33 (s, 1H).

Step 2 2-Amino-5-methylthiophene-3-carboxamide: The intermediate of Step 1 (25.5 g, 163.46 mmol) was added in portions to concentrated sulfuric acid (163 mL) with stirring and the mixture was added at 55 ° C. Heated for 1 hour. The reaction mixture was cooled to room temperature and poured into crushed ice. Aqueous ammonia was added to make the mixture basic. The separated solid was collected by filtration to give 16.8 g of product as a light brown solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.27 (s, 3H), 5.34 (br. s, 2H), 6.01 (br. s, 2H), 6.33 (s, 1H).

Step 3 6-Methylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione: To a stirred solution of the intermediate of Step 2 (16.5 g, 94.82 mmol) in anhydrous THF (316 mL) was added triphosgene. (14.07 g, 47.41 mmol) was added and the mixture was refluxed overnight under a nitrogen atmosphere. The mixture was cooled to room temperature and diluted with water (200 mL) with stirring. The precipitated solid was collected by filtration and dried to give 13.8 g of the desired product; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.36 (s, 3H), 6.82 (S, 1H), 11.07 (br. S, 1H), 11.79 (br. S, 1H).

Step 4 1,3,6-Trimethylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione: Intermediate of Step 3 (13.5 g, 74.17 mmol) in anhydrous DMF (148 mL) The solution was added to anhydrous K ₂ CO ₃ (51.25 g, 370.85 mmol) and the mixture was stirred at room temperature for 1 hour. Methyl iodide (34.74 g, 244.78 mmol) was slowly added with stirring, and the mixture was further stirred at room temperature for 24 hours. The reaction mixture was diluted with water and the precipitated solid was filtered, washed with water and dried to give 12.6 g of product as a brown solid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2 .42 (s, 3H), 3.22 (s, 3H), 3.42 (s, 3H), 6.90 (s, 1H).

Step 5 5-Iodo-1,3,6-trimethylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione: Boron of Step 4 intermediate (12.5 g, 59.52 mmol) N-iodosuccinimide (19.9 g, 89.28 mmol) was added to a stirred solution of trifluoride diethyl ether (300 mL), and the mixture was stirred at room temperature for 3 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (3 × 200 mL), the combined organic layers were washed with water (2 × 150 mL), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 2% ethyl acetate in chloroform to give 9.7 g of product as a light brown solid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.37 (s, 3H), 3.21 (s, 3H), 3.42 (s, 3H); MS (m / z) 337.11 (M + H) ⁺ .

Step 6 5-Allyl-1,3,6-trimethylthieno [2,3-d] pyrimidine-2,4 (1H, 3H) -dione: The compound is as described in Step 1 of Intermediate 1. Prepared. Intermediate of Step 5 (9.0 g) in the presence of tetrakis (triphenylphosphine) palladium (0) (3.09 g, 2.678 mmol) and cesium fluoride (8.13 g, 53.56 mmol) in anhydrous THF. , 26.78 mmol) was coupled with allylboronic acid pinacol ester (9.0 mL, 48.21 mmol) to give 4.5 g of the title compound as an off-white solid; ¹ H NMR (300 MHz, CDCl ₃ ) Δ 2.22 (s, 3H), 3.40 (s, 3H), 3.51 (s, 3H), 3.66 (d, J = 5.4 Hz, 2H), 5.00-4 .92 (m, 2H), 6.03-5.90 (m, 1H).

Step 7 (1,3,6-Trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetaldehyde: osmium tetroxide (in tert. Butanol 2.5 wt.%, 10 mg, 0.008 mmol) of Step 6 intermediate (1.0 g, 4.0 mmol) and sodium periodate (1.78 g, 8.48 mmol) in THF: H ₂ O (1 : 4, 80 mL) and the resulting mixture was stirred at room temperature for 6 hours. The reaction was quenched by the addition of a saturated solution of sodium thiosulfate and extracted with ethyl acetate (3 × 150 mL). The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ and the solvent was evaporated to give 0.92 g of the title compound as a white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.32 (s, 3H), 3.38 (s, 3H), 3.52 (s, 3H), 4.01 (s, 2H), 9.79 (br.s, 1H) .

Step 8 (1,3,6-Trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetic acid: intermediate of Step 7 (900 mg, To a solution of 3.57 mmol) and sulfamic acid (693 mg, 7.142 mmol) in acetone (17.8 mL) was added a solution of sodium chlorite (484 mg, 5.357 mmol) in water (5.35 mL) and the reaction mixture was Stir for 2 hours. The solvent was evaporated, diluted with water and acidified with 1N HCl. The resulting solid was collected by filtration and dried to give 375 mg of the title compound as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.30 (s, 3H), 3.20 (s, 3H), 3.42 (s, 3H), 3.80 (s, 2H), 12 .19 (br s, 1H); MS (m / z) 249.10 (M + H) ⁺ .

Intermediate 3
(6-Ethyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetic acid
This compound was prepared in 8 steps according to the procedure described above for preparing Intermediate 2, except that butyraldehyde was used in place of propionaldehyde in the first step. The compound was isolated as a white solid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.12-1.27 (m, 3H), 2.50-2.78 (m, 2H ), 3.23 (s, 3H), 3.43 (s, 3H), 3.80 (s, 2H), 12.19 (brs, 1H).

Intermediate 4
(1,3-Dimethyl-2,4-dioxo-6-propyl-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetic acid
This compound was prepared in 8 steps according to the procedure described above for preparing Intermediate 2, except that valeraldehyde was used in place of propionaldehyde in the first step. The compound was isolated as a white solid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.91 (t, J = 7.5 Hz, 3H), 1.51-1.60 ( m, 2H), 2.69 (t, J = 6.9 Hz, 2H), 3.20 (s, 3H), 3.35 (s, 3H), 3.79 (s, 2H), 12. 19 (br s, 1H).

Intermediate 5
(6-Isopropyl-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetic acid
This compound was prepared in 8 steps according to the procedure described above for preparing Intermediate 2, except that isovaleraldehyde was used in place of propionaldehyde in the first step. The compound was isolated as a white solid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.22 (d, J = 6.3 Hz, 6H), 3.20 (s, 3H) 3.32-3.38 (m, 1H, overlapped with DMSO peak), 3.44 (s, 3H), 3.83 (s, 2H), 12.19 (brs, 1H).

Intermediate 6
Ethyl (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) acetate
Step 1 1,3,6-Trimethylpyrimidine-2,4 (1H, 3H) -dione: N, N-dimethylurea (10.0 g, 113.588 mmol) and 4-dimethylaminopyridine (13.873 g, 113. Acetic anhydride (32.20 mL, 340.67 mmol) was added dropwise at 0 ° C. to a solution of 588 mmol) in anhydrous pyridine (30 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 2N HCl (250 mL) and extracted with chloroform (2 × 250 mL). The organic layer was washed with 1N HCl (100 mL), sodium bicarbonate solution (75 mL), and brine (75 mL) and dried (Na ₂ SO ₄ ). The solvent was evaporated under reduced pressure to give 10.25 g of product as a yellow solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.24 (s, 3H), 3.33 (s, 3H) 3.40 (s, 3H), 5.62 (s, 1H).

Step 2 5-acetyl-1,3,6-trimethylpyrimidine-2,4 (1H, 3H) -dione: Intermediate of Step 1 (10.0 g, 62.893 mmol), acetyl chloride (4.47 mL, 62. 893 mmol) and anhydrous zinc chloride (8.57 g, 62.893 mmol) in anhydrous benzene (150 mL) was refluxed for 48 hours. The solvent was completely evaporated under reduced pressure, diluted with water (500 mL) and extracted with chloroform (3 × 150 mL). The combined organic layers were washed with water (150 mL), dried (Na ₂ SO ₄ ) and concentrated. The resulting residue was purified by silica gel column chromatography by using 30% ethyl acetate in petroleum ether to give 4.7 g of product as a pale yellow solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.38 (s, 3H), 2.55 (s, 3H), 3.37 (s, 3H), 3.48 (s, 3H).

Step 3 1,3,5-Trimethylthieno [3,4-d] pyrimidine-2,4 (1H, 3H) -dione: Intermediate of Step 2 (3.0 g, 14.150 mmol) in absolute ethanol (56 mL) To the stirring solution, morpholine (1.854 mL, 21226 mmol), sulfur (679.2 mg, 21.226 mmol), and acetic acid (424 μL, 7.075 mmol) were added at room temperature. After refluxing for 72 hours, the reaction mixture was cooled to room temperature, diluted with water (150 mL) and extracted with ethyl acetate (150 mL). The combined organic layers were washed with sodium bicarbonate solution (75 mL), brine (50 mL), dried (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained after solvent evaporation was purified by silica gel column chromatography using 15% ethyl acetate in petroleum ether to give 1.5 g of product as an off-white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.87 (s, 3H), 3.39 (s, 3H), 3.46 (s, 3H), 6.25 (s, 1H).

Step 4 Diethyl (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) acetate: intermediate of Step 3 (2.3 g Sodium hydride (60% dispersion in mineral oil, 1.05 g, 26.29 mmol) was added to a stirred solution of 10.952 mmol) in diethyl carbonate (43 mL) and refluxed for 48 hours. The reaction mixture was cooled to room temperature, quenched with water and extracted with ethyl acetate (3 × 75 mL). The combined organic layers were washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated. The crude product was purified by silica gel column chromatography using 12% ethyl acetate in petroleum ether to give 1.56 g of product as a yellow solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1 .30 (t, J = 6.9 Hz, 6H), 3.39 (s, 3H), 3.48 (s, 3H), 4.20-4.31 (m, 4H), 6.40 ( s, 1H), 6.58 (s, 1H).

Step 5 Ethyl (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) acetate: intermediate of Step 4 (1.5 g To a stirred solution of 4.237 mmol) in absolute ethanol (17 mL), a catalytic amount of sodium hydride (60% dispersion in mineral oil, 16.94 mg, 0.423 mmol) was added at room temperature and refluxed for 2 hours. The solvent was completely evaporated under reduced pressure and diluted with water, and the resulting solid was collected by filtration and dried to give 615 mg of product as an off-white solid; ¹ H NMR (300 MHz, CDCl ₃ ) δ 1 .29 (t, J = 7.2 Hz, 3H), 3.38 (s, 3H), 3.47 (s, 3H), 4.22 (q, J = 7.2 Hz, 2H), 4 .37 (s, 2H), 6.44 (s, 1H).

General Procedure Method 1 for Preparing 2-Amino-4-arylthiazole 1
To a solution of acetophenone derivative (1.0 eq) in glacial acetic acid (5 vol) was added liquid bromine (1.0 eq) at 0 ° C. and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine, and dried over Na ₂ SO ₄ . The crude product obtained by concentration was dissolved in anhydrous THF (10 vol), thiourea (2.0 eq) was added and refluxed overnight. The reaction mixture was diluted with ethyl acetate, washed with sodium thiosulfate solution, and the organic layer was treated with 1N HCl to form an amine salt. The precipitated salt was collected by filtration. The salt was then treated with a saturated NaHCO ₃ solution to regenerate the amine. The mixture was extracted with dichloromethane (2 × 50 mL) and the combined organic extracts were washed with water and brine. The solvent was distilled off under reduced pressure to obtain a 2-amino-4-aryl-thiazole derivative.

Method 2
A solution of acetophenone derivative (1.0 eq), thiourea (2.0 eq), and iodine (1.0 eq) in absolute ethanol (5 vol) was refluxed for 24 hours. The reaction mixture was diluted with ethyl acetate and the layers were separated. The organic layer was washed with sodium thiosulfate solution to remove iodine. The ethyl acetate solution was treated with 1N HCl and the precipitated salt was collected by filtration. The free amine was regenerated as described in Method 1 above.

All 2-amino-4-arylthiazole derivatives were prepared by either Method 1 or Method 2, starting from the appropriate aryl alkyl ketone. The structural information and characterization data for the selected intermediate are shown in Table 1.

Preparation of 4- [3-fluoro-4- (trifluoromethyl) phenyl] -1H-imidazol-2-amine:
Step 1 N- {4- [3-Fluoro-4- (trifluoromethyl) phenyl] -1H-imidazol-2-yl} acetamide: 2-bromo-1- [3-fluoro-4- (trifluoromethyl) To a stirred solution of phenyl] ethanone (4.5 g, 15.73 mmol) in acetonitrile (45 mL) was added acetylguanidine (2.38 g, 23.60 mmol) at room temperature. After refluxing for 4 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate and water. The layers were separated. The aqueous layer was extracted 2-3 times with ethyl acetate and the combined organic layers were washed with water, then with brine, dried (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained after evaporation of the solvent was purified by silica gel column chromatography using 2% methanol in chloroform to give 1.15 g of product as a yellow solid; ¹ H NMR (300 MHz, DMSO- d ₆ ) δ 2.07 (s, 3H), 7.58 (s, 1H), 7.69-7.78 (m, 3H), 11.31 (br s, 1H), 11.91 (br s, 1H).

Step 2 4- [3-Fluoro-4- (trifluoromethyl) phenyl] -1H-imidazol-2-amine: Intermediate of Step 1 (1.1 g, 3.829 mmol) in methanol (20 mL) and water (20 mL) Concentrated H ₂ SO ₄ (2 mL) was added to a stirred solution of the mixture, and the resulting mixture was refluxed for 24 hours. The reaction mixture was cooled to room temperature, basified with calcium carbonate (pH = 10) and extracted with ethyl acetate (2 × 50 mL). The organic layer was dried (Na ₂ SO ₄ ) and filtered. The filtrate was concentrated under reduced pressure. The residue obtained after evaporation of the solvent was purified by silica gel column chromatography using 5% methanol in chloroform to give 290 mg of product as a yellow solid; ¹ H NMR (300 MHz, DMSO-d ₆ ) 5.55 (br s, 2H), 7.32 (s, 1H), 7.59-7.67 (m, 3H), 11.30 (br s, 1H).

Preparation of 4- [3- (trifluoromethoxy) phenyl] -1H-imidazol-2-amine:
Step 1 N- {4- [3- (trifluoromethoxy) phenyl] -1H-imidazol-2-yl} acetamide: 2-bromo-1- [3- (trifluoromethoxy) phenyl] ethanone (1.7 g, The title compound was prepared according to the described procedure using a solution of 6.00 mmol) and acetylguanidine (0.91 g, 9.01 mmol) in acetonitrile (17 mL) to give 460 g of product as a yellow solid; ¹ H NMR ( 300 MHz, CDCl ₃ ) δ 2.07 (s, 3H), 5.50 (s, 1H), 7.10-7.15 (m, 1H), 7.39 (t, J = 7.8, 1H), 7.47-7.64 (m, 3H), 7.92 (s, 1H).

Step 2 4- [3- (Trifluoromethoxy) phenyl] -1H-imidazol-2-amine: A mixture of the intermediate of Step 1 (450 mg, 1.578 mmol) in methanol-water (22 mL) and concentrated H ₂ SO ₄ ( The title compound was prepared following the described procedure using 1 mL) to give 130 g of product as a yellow solid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 5.75 (br s, 2H), 7 .08 (d, J = 8.1, 1H), 7.21 (s, 1H), 7.41 (t, J = 7.8, 1H), 7.55-7.64 (m, 2H) 11.30 (br s, 1H).

Preparation of 1- (4-bromophenyl) -1H-pyrazol-3-amine
The title compound was prepared by reacting 4-bromophenylhydrazine with acrylonitrile in refluxing ethanol in the presence of a suitable base such as sodium ethoxide followed by oxidation with N-bromosuccinimide; ¹ H NMR ( 300 MHz, DMSO-d ₆ ) δ 3.81 (br s, 2H), 5.84 (s, 1H), 7.41 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.7 Hz, 2H), 7.63 (s, 1H).

By reacting 4-bromoacetophenone with N, N-dimethylformamide dimethyl acetal followed by cyclization with guanidine hydrochloride in the presence of a suitable base such as potassium carbonate in refluxing dimethylene glycol monoethyl ether . - (4-Bromophenyl) pyrimidin-2-amine was prepared. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 6.69 (br s, 2H), 7.11 (d, J = 5.1 Hz, 1H), 7.67 (d, J = 8.4) Hz, 2H), 7.9 (d, J = 8.1 Hz, 2H), 8.29 (d, J = 4.8, 1H).

  3- (4-chlorophenyl) isoxazol-5-amine, 5- (4-bromophenyl) isoxazol-3-amine, 3- (4-chlorophenyl) -1H-pyrazol-5-amine used in the synthesis, and 5- (4-Bromophenyl) -1,3,4-thiadiazol-2-amine is a commercial product and was purchased from Aldrich.

  The exemplary compounds described herein were synthesized by coupling thienopyrimidineacetic acid derivatives with the appropriate arylamine.

General Procedure for Preparation of the Examples Method A:
To a stirred solution of carboxylic acid derivative (1.0 eq) in 1,2-dichloroethane, EDCI (1.2 eq), HOBt (0.3 eq), and 4-dimethylaminopyridine (0.1 eq) were added. The mixture was stirred at room temperature for 10-15 minutes. Subsequently, the appropriate amine (1.0 eq) was added and the mixture was stirred at the same temperature for 48 hours. The solvent was evaporated under reduced pressure and the resulting residue was diluted with methanol and stirred at room temperature for 30 minutes. The separated solid was collected by filtration. The solid product was further purified by recrystallization from isopropanol or methanol to give the desired product.

Method B:
EDCI (2.0 eq) was added to a stirred solution of a mixture of carboxylic acid derivative (1.0 eq) in tetrahydrofuran and N, N-dimethylformamide (3: 1) and the mixture was stirred for 30 min. Appropriate amine (1.0 eq) and DMAP (0.2 eq) were added and the mixture was maintained at 80 ° C. under stirring for an additional 24 hours. Most of the tetrahydrofuran was evaporated under reduced pressure and the mixture was acidified to pH 6.0 by adding 2N hydrochloric acid. The precipitated solid was collected by filtration. The product was further purified by crystallization or silica gel column chromatography using a methanol-chloroform mixture.

Method C:
Sodium hydride was added to a stirred solution of the appropriate thiazoleamine (1.2 eq) in anhydrous toluene and the mixture was stirred at room temperature for 30 minutes. Thienopyrimidine acetate (1.0 eq) was added and the mixture was heated to reflux overnight. The mixture was cooled and acidified to pH 6.0 by adding 2N hydrochloric acid. The precipitated solid was collected by filtration. The product was further purified by crystallization or silica gel column chromatography using a methanol-chloroform mixture.

Example 1
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) -N- [4- (trifluoromethyl)- 1,3-thiazol-2-yl] acetamide
In the presence of EDCI hydrochloride (90 mg, 0.471 mmol), HOBt (16 mg, 0.118 mmol) and DMAP (5 mg, 0.039 mmol) in 1,2-dichloroethane (4 mL), intermediate 1 (100 mg, 0 .393 mmol) and 4- (trifluoromethyl) -1,3-thiazol-2-amine (66 mg, 0.393 mmol) were coupled to give 27 mg of product as a white solid. The title compound was prepared according to the procedure (Method A); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.18 (s, 3H), 3.46 (s, 3H), 4.05 (s, 2H ), 7.07 (s, 1H), 7.91 (s, 1H), 12.70 (br s, 1H); APCI-MS (m / z) 40 .97 (M + ^H) +.

Example 2
N- [4- (4-Chlorophenyl) -1,3-thiazol-2-yl] -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2, 3-d] pyrimidin-5-yl) acetamide
Intermediate 1 (200 mg) in the presence of EDCI hydrochloride (163 mg, 0.851 mmol), HOBt (28 mg, 0.212 mmol) and DMAP (8.60 mg, 0.079 mmol) in 1,2-dichloroethane (4 mL). , 0.709 mmol) and 4- (4-chlorophenyl) -1,3-thiazol-2-amine (149 mg, 0.709 mmol) to give 95 mg of product as an off-white solid. The title compound was prepared according to the general procedure (Method A); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.47 (s, 3H), 4.06 ( s, 2H), 7.07 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.66 (s, 1H), 7.92 (d, J = 8.4 Hz, 2H), 12.41 (br s, 1H); APCI-MS (m / z) 445.27 (M + H) ⁺ .

Example 3
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) -N- {4- [3- (trifluoro Methoxy) phenyl] -1,3-thiazol-2-yl} acetamide
Intermediate 1 (150 mg) in the presence of EDCI hydrochloride (135 mg, 0.708 mmol), HOBt (24 mg, 0.177 mmol) and DMAP (7.21 mg, 0.059 mmol) in 1,2-dichloroethane (6 mL). , 0.590 mmol) and 4- [3- (trifluoromethoxy) phenyl] -1,3-thiazol-2-amine (155 mg, 0.590 mmol) to give 40 mg of product as a white solid The title compound was prepared according to the general procedure (Method A) by obtaining ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.47 (s, 3H), 4.07 (s, 2H), 7.07 (s, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.58 (t J = 7.8 Hz, 1H), 7.78 (s, 1H), 7.87 (s, 1H), 7.94 (d, J = 8.1 Hz, 1H), 12.44 (br s) , 1H); ESI-MS (m / z) 497.03 (M + H) ⁺ .

Example 4
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) -N- [4- (4-isobutylphenyl) -1,3-thiazol-2-yl] acetamide
In the presence of EDCI hydrochloride (90 mg, 0.472 mmol), HOBt (16 mg, 0.117 mmol) and DMAP (5 mg, 0.039 mmol) in 1,2-dichloroethane (4 mL), intermediate 1 (100 mg, 0 393 mmol) and 4- (4-isobutylphenyl) -1,3-thiazol-2-amine (91 mg, 0.393 mmol) to give 42 mg of product as a white solid. The title compound was prepared according to the general procedure (Method A); ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.88 (d, J = 6.3 Hz, 6H), 1.83-1.90 (m, 1H), 2.48 (d, J = 6.9 Hz, 2H), 3.51 (s, 3H), 3.57 (s, 3H), 4.06 (s 2H), 6.88 (s, 1H), 7.04 (s, 1H), 7.16 (d, J = 7.8 Hz, 2H), 7.72 (d, J = 7.8 Hz, 2H), 10.73 (br s, 1H); APCI-MS (m / z) 469.14 (M + H) ⁺ .

Example 5
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) -N- {4- [ 3 -fluoro- 4 -(Trifluoromethyl) phenyl] -1,3-thiazol-2-yl} acetamide
Intermediate 1 (102 mg, 0,40 mg) in the presence of EDCI hydrochloride (92 mg, 0.481 mmol), HOBt (16 mg, 0.120 mmol) and DMAP (5 mg, 0.040 mmol) in 1,2-dichloroethane (4 mL). .401 mmol) and 4- [3-fluoro-4- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine (105 mg, 0.401 mmol) were coupled to give 16 mg of white solid The title compound was prepared according to the general procedure (Method A) by obtaining the product; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.47 (s, 3H ), 4.07 (s, 2H), 7.07 (s, 1H), 7.83-8.01 (m, 4H), 12.51 (br , 1H); ESI-MS ( m / z) 499.05 (M + H) +.

Example 6
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) -N- {4- [4-fluoro-3 -(Trifluoromethyl) phenyl] -1,3-thiazol-2-yl} acetamide
Intermediate 1 (102 mg, 0,40 mg) in the presence of EDCI hydrochloride (92 mg, 0.481 mmol), HOBt (16 mg, 0.120 mmol) and DMAP (5 mg, 0.040 mmol) in 1,2-dichloroethane (4 mL). .401 mmol) and 4- [4-fluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine (105 mg, 0.401 mmol) were coupled to yield 23 mg of white solid. The title compound was prepared according to the general procedure (Method A) by obtaining the product; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.47 (s, 3H ), 4.06 (s, 2H), 7.07 (s, 1H), 7.64 (t, J = 9.0 Hz, 1H), 7.83 s, 1H), 8.08-8.36 (m , 2H), 12.48 (br s, 1H); ESI-MS (m / z) 499.10 (M + H) +.

Example 7
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) -N- {4- [2-fluoro-4 -(Trifluoromethyl) phenyl] -1,3-thiazol-2-yl} acetamide
Intermediate 1 (150 mg) in the presence of EDCI hydrochloride (135 mg, 0.708 mmol), HOBt (24 mg, 0.177 mmol) and DMAP (7.21 mg, 0.059 mmol) in 1,2-dichloroethane (6 mL). , 0.590 mmol) and 4- [2-fluoro-4- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine (155 mg, 0.590 mmol) as a white solid The title compound was prepared according to the general procedure (Method A) by obtaining 35 mg of product; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.47 (s 3H), 4.08 (s, 2H), 7.08 (s, 1H), 7.70-7.84 (m, 3H), 8.23- .28 (m, 1H), 12.52 (br s, 1H); APCI-MS (m / z) 497.21 (M + H) +.

Example 8
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) -N- {4- [3-fluoro-5 -(Trifluoromethyl) phenyl] -1,3-thiazol-2-yl} acetamide
In the presence of EDCI hydrochloride (90 mg, 0.471 mmol), HOBt (16 mg, 0.117 mmol) and DMAP (5 mg, 0.039 mmol) in 1,2-dichloroethane (6 mL), intermediate 1 (100 mg, 0 .393 mmol) and 4- [3-fluoro-5- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine (103 mg, 0.393 mmol) were coupled to yield 21 mg of a white solid. The title compound was prepared according to the general procedure (Method A) by obtaining the product; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.47 (s, 3H ), 4.07 (s, 2H), 7.07 (s, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.97 s, 1H), 8.06 (d, J = 9.0 Hz, 1H), 8.13 (s, 1H), 12.49 (brs, 1H); APCI-MS (m / z) 497. 20 (M−H) ⁻ .

Example 9
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) -N- {4- [2-fluoro-3 -(Trifluoromethyl) phenyl] -1,3-thiazol-2-yl} acetamide
In the presence of EDCI hydrochloride (90 mg, 0.472 mmol), HOBt (16 mg, 0.117 mmol) and DMAP (5 mg, 0.039 mmol) in 1,2-dichloroethane (6 mL), intermediate 1 (100 mg, 0 .393 mmol) and 4- [2-fluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine (103 mg, 0.393 mmol) were coupled to give 40 mg as an off-white solid. The title compound was prepared according to the general procedure (Method A) by obtaining the product of: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.47 (s, 3H), 4.08 (s, 2H), 7.07 (s, 1H), 7.53 (t, J = 7.5 Hz, 1H), 7 .66 (s, 1H), 7.77 (t, J = 6.9 Hz, 1H), 8.30-8.37 (m, 1H), 12.49 (brs, 1H); APCI-MS (M / z) 499.51 (M + H) ^<+> .

Example 10
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) -N- {4- [4-fluoro-3 -(Trifluoromethoxy) phenyl] -1,3-thiazol-2-yl} acetamide
In the presence of EDCI hydrochloride (90 mg, 0.472 mmol), HOBt (16 mg, 0.118 mmol) and DMAP (5 mg, 0.039 mmol) in 1,2-dichloroethane (4 mL), intermediate 1 (100 mg, 0 .393 mmol) and 4- [4-fluoro-3- (trifluoromethoxy) phenyl] -1,3-thiazol-2-amine (109 mg, 0.393 mmol) were coupled to give 35 mg as an off-white solid. The title compound was prepared according to the general procedure (Method A) by obtaining the product of: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.47 (s, 3H), 4.06 (s, 2H), 7.07 (s, 1H), 7.59 (t, J = 8.7 Hz, 1H), 7.76 (s, 1H), 8.00-8.06 (m, 2H), 12.44 (brs, 1H); APCI-MS (m / z) 513.11 (M-H) ⁻ .

Example 11
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) -N- {4- [3-fluoro-4 -(Trifluoromethoxy) phenyl] -1,3-thiazol-2-yl} acetamide
In the presence of EDCI hydrochloride (90 mg, 0.471 mmol), HOBt (16 mg, 0.117 mmol) and DMAP (5 mg, 0.039 mmol) in 1,2-dichloroethane (4 mL), intermediate 1 (100 mg, 0 .393 mmol) and 4- [3-fluoro-4- (trifluoromethoxy) phenyl] -1,3-thiazol-2-amine (109 mg, 0.393 mmol) were coupled to give 35 mg of white solid The title compound was prepared according to the general procedure (Method A) by obtaining the product; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.47 (s, 3H ), 4.07 (s, 2H), 7.07 (s, 1H), 7.64 (t, J = 8.1 Hz, 1H), 7.80 (S, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.93-8.01 (m, 1H), 12.45 (br s, 1H); APCI-MS (m / Z) 515.02 (M + H) ⁺ .

Example 12
N- [4- (3,4-Dichlorophenyl) -1,3-thiazol-2-yl] -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [ 2,3-d] pyrimidin-5-yl) acetamide
In the presence of EDCI hydrochloride (90 mg, 0.471 mmol), HOBt (16 mg, 0.118 mmol) and DMAP (5 mg, 0.039 mmol) in 1,2-dichloroethane (4 mL), intermediate 1 (100 mg, 0 .393 mmol) and 4- (3,4-dichlorophenyl) -1,3-thiazol-2-amine (96.5 mg, 0.393 mmol) to give 40 mg of product as a white solid. The title compound was prepared according to the general procedure (Method A) by ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.47 (s, 3H), 4.06 (S, 2H), 7.07 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.80 (s, 1H), 7.89 (D, J = 6.9 Hz, 1H), 8.14 (s, 1H), 12.43 (brs, 1H); APCI-MS (m / z) 479.32 (M-H) ⁺ .

Example 13
N- {4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide
In the presence of EDCI hydrochloride (90 mg, 0.471 mmol), HOBt (16 mg, 0.117 mmol) and DMAP (5 mg, 0.039 mmol) in 1,2-dichloroethane (4 mL), intermediate 1 (100 mg, 0 393 mmol) and 4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine (110 mg, 0.393 mmol) as a white solid The title compound was prepared according to the general procedure (Method A) by obtaining 20 mg of product; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.47 (s 3H), 4.07 (s, 2H), 7.08 (s, 1H), 7.55 (t, J = 9.0 Hz, 1H), 62 (s, 1H), 8.34 (q, J = 6.9 Hz, 1H), 12.50 (br s, 1H); ESI-MS (m / z) 517.09 (M + H) ⁺ .

Example 14
[N- {4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1 , 2,3,4-Tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamido] sodium
Example 13 To a solution of (50 mg, 0.096 mmol) in anhydrous THF (1 mL) was added sodium hydride (60% dispersion in mineral oil, 5 mg, 0.106 mmol) at room temperature and stirred for 2 hours. Excess solvent was removed under reduced pressure and the resulting solid was washed with hexane (2 × 5 mL), anhydrous diethyl ether (5 mL) and dried thoroughly to give 50 mg of product as an off-white solid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.23 (s, 3H), 3.46 (s, 3H), 3.81 (s, 2H), 6.89 (s, 1H), 7 .04 (s, 1H), 7.40 (t, J = 9.6 Hz, 1H), 8.41 (q, J = 6.9 Hz, 1H); ESI-MS (m / z) 517. 09 (M + H) ⁺ .

Example 15
N- {4- [2,3-difluoro-4- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide
In the presence of EDCI hydrochloride (90 mg, 0.472 mmol), HOBt (16 mg, 0.117 mmol) and DMAP (5 mg, 0.039 mmol) in 1,2-dichloroethane (4 mL), intermediate 1 (100 mg, 0 393 mmol) and 4- [2,3-difluoro-4- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine (110 mg, 0.393 mmol) were coupled to an off-white solid The title compound was prepared according to the general procedure (Method A) by obtaining 27 mg of product as: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.47 ( s, 3H), 4.08 (s, 2H), 7.08 (s, 1H), 7.70-7.80 (m, 2H), 7. 8-8.04 (m, 1H), 12.56 (br s, 1H); APCI-MS (m / z) 517.06 (M + H) +.

Example 16
N- {4- [3,5-difluoro-4- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide
In the presence of EDCI hydrochloride (90 mg, 0.472 mmol), HOBt (16 mg, 0.117 mmol) and DMAP (5 mg, 0.039 mmol) in 1,2-dichloroethane (4 mL), intermediate 1 (100 mg, 0 393 mmol) and 4- [3,5-difluoro-4- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine (110 mg, 0.393 mmol) were coupled to an off-white solid. The title compound was prepared according to the general procedure (Method A) by obtaining 30 mg of product as: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.47 ( s, 3H), 4.07 (s, 2H), 7.07 (s, 1H), 7.83 (s, 1H), 7.87 (s, 1H), 8.06 (s, 1H), 12.51 (brs, 1H); APCI-MS (m / z) 517.01 (M + H) ⁺ .

Example 17
N- [4- (4-tert-butylphenyl) -1,3-thiazol-2-yl] -2- (1,3,6-trimethyl-2,4-dioxo-1,2,3,4- Tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide
In the presence of EDCI hydrochloride (85 mg, 0.447 mmol), HOBt (15 mg, 0.111 mmol) and DMAP (5 mg, 0.037 mmol) in 1,2-dichloroethane (4 mL), intermediate 2 (100 mg, 0 373 mmol) and 4- (4-tert-butylphenyl) -1,3-thiazol-2-amine (86 mg, 0.373 mmol) to give 38 mg of product as a white solid. The title compound was prepared according to the general procedure (Method A); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.30 (s, 9H), 2.35 (s, 3H), 3.18 ( s, 3H), 3.44 (s, 3H), 4.05 (s, 2H), 7.45 (d, J = 7.8 Hz, 2H), 7.51 (S, 1H), 7.82 (d, J = 7.8 Hz, 2H), 12.39 (s, 1H); APCI-MS (m / z) 483.05 (M + H) ^<+> .

Example 18
N- {4- [3- (trifluoromethoxy) phenyl] -1,3-thiazol-2-yl} -2- (1,3,6-trimethyl-2,4-dioxo-1,2,3 4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide
In the presence of EDCI hydrochloride (85 mg, 0.447 mmol), HOBt (15 mg, 0.111 mmol) and DMAP (5 mg, 0.037 mmol) in 1,2-dichloroethane (4 mL), intermediate 2 (100 mg, 0 .373 mmol) and 4- (3-trifluoromethoxyphenyl) -1,3-thiazol-2-amine (97 mg, 0.373 mmol) to give 21 mg of product as a white solid. The title compound was prepared according to the general procedure (Method A); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.36 (s, 3H), 3.18 (s, 3H), 3.44 ( s, 3H), 4.06 (s, 2H), 7.33 (d, J = 7.2 Hz, 1H), 7.58 (t, J = 7.8) z, 1H), 7.78 (s, 1H), 7.97-7.85 (m, 2H), 12.45 (s, 1H); APCI-MS (m / z) 511.02 (M + H) ⁺ .

Example 19
N- [4- (4-Chlorophenyl) -1,3-thiazol-2-yl] -2- (1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [ 2,3-d] pyrimidin-5-yl) acetamide
Intermediate 2 (200 mg) in the presence of EDCI hydrochloride (171 mg, 0.895 mmol), HOBt (30 mg, 0.223 mmol) and DMAP (9.11 mg, 0.074 mmol) in 1,2-dichloroethane (4 mL). , 0.746 mmol) and 4- (4-chlorophenyl) -1,3-thiazol-2-amine (157 mg, 0.746 mmol) to give 13 mg of product as a yellow solid, The title compound was prepared according to the general procedure (Method A); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.36 (s, 3H), 3.18 (s, 3H), 3.44 (s 3H), 4.06 (s, 2H), 7.50 (d, J = 8.7 Hz, 2H), 7.65 (s, 1H), 7.92. (D, J = 8.4 Hz, 2H), 12.40 (br s, 1H); APCI-MS (m / z) 461.11 (M + H) ⁺ .

Example 20
N- [4- (3,4-Dichlorophenyl) -1,3-thiazol-2-yl] -2- (1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydro Thieno [2,3-d] pyrimidin-5-yl) acetamide
Intermediate 2 (100 mg) in the presence of EDCI hydrochloride (85 mg, 0.445 mmol), HOBt (15 mg, 0.111 mmol) and DMAP (5 mg, 0.037 mmol) in 1,2-dichloroethane (3.7 mL). , 0.373 mmol) and 4- (3,4-dichlorophenyl) -1,3-thiazol-2-amine (91 mg, 0.373 mmol) to give 13 mg of product as a white solid. The title compound was prepared according to the general procedure (Method A) by ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.36 (s, 3H), 3.18 (s, 3H), 3.44 (S, 3H), 4.06 (s, 2H), 7.71 (d, J = 8.1 Hz, 1H), 7.81 (s, 1H), 7.89 (D, J = 8.1 Hz, 1H), 8.15 (s, 1H), 12.45 (brs, 1H). APCI-MS (m / z) 495.40 (M + H) ^<+> .

Example 21
N- [4- (2,3-difluorophenyl) -1,3-thiazol-2-yl] -2- (1,3,6-trimethyl-2,4-dioxo-1,2,3,4- Tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide
In the presence of EDCI hydrochloride (85 mg, 0.447 mmol), HOBt (15 mg, 0.111 mmol) and DMAP (5 mg, 0.037 mmol) in 1,2-dichloroethane (4 mL), intermediate 2 (100 mg, 0 .373 mmol) and 4- (2,3-difluorophenyl) -1,3-thiazol-2-amine (80 mg, 0.373 mmol) to give 15 mg of product as an off-white solid. The title compound was prepared according to the general procedure (Method A) by ¹ H NMR (300 MHz, DMSO-d ₆ ) 2.36 (s, 3H), 3.18 (s, 3H); s, 3H), 4.06 (s, 2H), 7.28-7.46 (m, 2H), 7.59 (s, 1H), 7.78-7 87 (m, 1H), 12.48 (br s, 1H). APCI-MS (m / z) 510.95 (M + H) ^<+> .

Example 22
N- [4- (2,4-difluorophenyl) -1,3-thiazol-2-yl] -2- (1,3,6-trimethyl-2,4-dioxo-1,2,3,4- Tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide
Intermediate 2 (100 mg) in the presence of EDCI hydrochloride (85 mg, 0.447 mmol), HOBt (15 mg, 0.111 mmol) and DMAP (4.5 mg, 0.037 mmol) in 1,2-dichloroethane (3 mL). , 0.373 mmol) and 4- (2,4-difluorophenyl) -1,3-thiazol-2-amine (97 mg, 0.373 mmol) to give 25 mg of product as a white solid. The title compound was prepared according to the general procedure (Method A) by: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.36 (s, 3H), 3.18 (s, 3H); 44 (s, 3H), 4.06 (s, 2H), 7.22 (t, J = 6.6 Hz, 1H), 7.33-7.41 (m, 1H , 7.46 (s, 1H), 8.06 (d, J = 7.2 Hz, 1H), 12.43 (br s, 1H); ESI-MS (m / z) 463.06 (M + H) ⁺ .

Example 23
N- {4- [4-Fluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3,6-trimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide
Intermediate 2 in the presence of EDCI hydrochloride (85 mg, 0.445 mmol), HOBt (15 mg, 0.111 mmol) and DMAP (4.5 mg, 0.037 mmol) in 1,2-dichloroethane (3.7 mL). (100 mg, 0.373 mmol) and 4- [4-fluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine (97 mg, 0.373 mmol) were coupled to give white The title compound was prepared according to the general procedure (Method A) by obtaining 28 mg of product as a solid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.36 (s, 3H), 3.18 (S, 3H), 3.44 (s, 3H), 4.06 (s, 2H), 7.61 (d, J = 9.0 Hz, 1H), 7. 82 (s, 1H), 8.24-8.30 (m, 2H), 12.47 (br s, 1H); APCI-MS (m / z) 513.09 (M + H) ⁺ .

Example 24
N- {4- [3-Fluoro-4- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3,6-trimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide
In the presence of EDCI hydrochloride (85 mg, 0.447 mmol), HOBt (15 mg, 0.111 mmol) and DMAP (5 mg, 0.037 mmol) in 1,2-dichloroethane (4 mL), intermediate 2 (100 mg, 0 .373 mmol) and 4- [3-fluoro-4- (trifluoromethyl) phenyl-1,3-thiazol-2-amine (97 mg, 0.373 mmol) were coupled to yield 24 mg as a white solid The title compound was prepared according to the general procedure (Method A) by obtaining the product; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.36 (s, 3H), 3.18 (s, 3H) 3.44 (s, 3H), 4.06 (s, 2H), 8.01-7.85 (m, 4H), 12.49 (s, 1H) ; APCI-MS (m / z ) 513.14 (M + H) +.

Example 25
N- {4- [4-Fluoro-3- (trifluoromethoxy) phenyl] -1,3-thiazol-2-yl} -2- (1,3,6-trimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide
Intermediate 2 in the presence of EDCI hydrochloride (154 mg, 0.805 mmol), HOBt (27.2 mg, 0.201 mmol) and DMAP (8.19 mg, 0.0071 mmol) in 1,2-dichloroethane (7 mL). (180 mg, 0.671 mmol) and 4- [4-fluoro-3- (trifluoromethoxy) phenyl] -1,3-thiazol-2-amine (187 mg, 0.671 mmol) were coupled off-white. The title compound was prepared according to the general procedure (Method A) by obtaining 17.5 mg of product as a solid of ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.35 (s, 3H), 3.18 (s, 3H), 3.44 (s, 3H), 4.06 (s, 2H), 7.58 (t, J = 9. 0 Hz, 1H), 7.74 (s, 1H), 8.00-8.06 (m, 2H), 12.40 (brs, 1H); APCI-MS (m / z) 529.00 ( M + H) ⁺ .

Example 26
N- {4- [3-Fluoro-4- (trifluoromethoxy) phenyl] -1,3-thiazol-2-yl} -2- (1,3,6-trimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide
Intermediate 1 in the presence of EDCI hydrochloride (154 mg, 0.805 mmol), HOBt (27.2 mg, 0.201 mmol) and DMAP (8.19 mg, 0.0071 mmol) in 1,2-dichloroethane (7 mL). (180 mg, 0.671 mmol) and 4- [3-fluoro-4- (trifluoromethoxy) phenyl] -1,3-thiazol-2-amine (187 mg, 0.671 mmol) were coupled off-white. The title compound was prepared according to the general procedure (Method A) by obtaining 54 mg of product as a solid of ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.36 (s, 3H), 18 (s, 3H), 3.44 (s, 3H), 4.06 (s, 2H), 7.65 (t, J = 9.3) z, 1H), 7.80 (s, 1H), 7.85 (d, J = 8.7 Hz, 1H), 7.98 (d, J = 9.0, 1H), 12.47 (br s, 1H); APCI-MS (m / z) 529.06 (M + H) ^<+> .

Example 27
N- {4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3,6-trimethyl-2,4-dioxo- 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide
In the presence of EDCI hydrochloride (214 mg, 1.119 mmol) and DMAP (13.5 mg, 0.119 mmol) in a THF: DMF (3: 1) mixture (2.8 mL), intermediate 2 (150 mg, 0.1. 559 mmol) and 4- (2,4-difluoro-3- (trifluoromethyl) phenyl) -1,3-thiazol-2-amine (156 mg, 0.559 mmol) as an off-white solid. The title compound was prepared according to the general procedure (Method B) by obtaining 27 mg of product; ¹ H NMR (300 MHz, CDCl ₃ ) δ 2.55 (s, 3H), 3.53 (2 s, 6H ), 4.04 (s, 2H), 7.07 (t, J = 9.0 Hz, 1H), 7.38 (s, 1H), 8.33 (q, J = 8.7 Hz, 1H), 10.96 (br s, 1H); APCI-MS (m / z) 513.14 (M + H) ⁺ .

Example 28
N- [4- (3-trifluoromethoxyphenyl) -1H-imidazol-2-yl] -2- (1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide
Intermediate 2 (140 mg) in the presence of EDCI hydrochloride (120 mg, 0.626 mmol), HOBt (21 mg, 0.156 mmol) and DMAP (6.38 mg, 0.052 mmol) in 1,2-dichloroethane (4 mL). , 0.522 mmol) and 4- [3- (trifluoromethoxy) phenyl] -1H-imidazol-2-amine (126 mg, 0.522 mmol) to give 30 mg of product as an off-white solid. The title compound was prepared according to the general procedure (Method A) by obtaining ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.36 (s, 3H), 3.20 (s, 3H), 3 .44 (s, 3H), 4.10 (s, 2H), 7.10-7.16 (m, 1H), 7.39-7. 0 (m, 2H), 7.68 (s, 1H), 7.72-7.80 (m, 1H), 11.38 (br s, 1H), 11.68 (br s, 1H); APCI -MS (m / z) 494.11 (M + H) ^<+> .

Example 29
N- {4- [3-Fluoro-4- (trifluoromethyl) phenyl] -1H-imidazol-2-yl} -2- (1,3,6-trimethyl-2,4-dioxo-1,2, 3,4-Tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide
Intermediate 2 (150 mg) in the presence of EDCI hydrochloride (128 mg, 0.671 mmol), HOBt (22 mg, 0.167 mmol) and DMAP (6.83 mg, 0.055 mmol) in 1,2-dichloroethane (6 mL). , 0.559 mmol) and 4- [3-fluoro-4- (trifluoromethyl) phenyl] -1H-imidazol-2-amine (137 mg, 0.559 mmol) were coupled as an off-white solid. The title compound was prepared according to the general procedure (Method A) by obtaining .5 mg of product; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 2.36 (s, 3H), 3.20 ( s, 3H), 3.44 (s, 3H), 3.98 (s, 2H), 7.57 (s, 1H), 7.70 7.80 (m, 3H), 11.40 (br s, 1H), 11.83 (br s, 1H); APCI-MS (m / z) 496.26 (M + H) +.

Example 30
N- [4- (4-Cyanophenyl) -1,3-thiazol-2-yl] -2- (6-ethyl-1,3-dimethyl-2,4-dioxo-1,2,3,4- Tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide
In the presence of EDCI hydrochloride (122 mg, 0.638 mmol), HOBt (21 mg, 0.159 mmol) and DMAP (6.4 mg, 0.053 mmol) in 1,2-dichloroethane (5.3 mL), intermediate 3 (150 mg, 0.531 mmol) and 4- (4-cyanophenyl) -1,3-thiazol-2-amine (107 mg, 0.531 mmol) were coupled to give 10 mg of product as an off-white solid. The title compound was prepared according to the general procedure (Method A); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.19 (t, J = 7.5 Hz, 3H), 2.79. (Q, J = 7.8, 2H), 3.18 (s, 3H), 3.47 (s, 3H), 4.07 (s, 2H), 7.87 −7.93 (m, 3H), 8.09 (d, J = 8.4 Hz, 2H), 12.48 (br s, 1H); ESI-MS (m / z) 464.31 (M−) H) ⁻ .

Example 31
N- {4- [3-Fluoro-4- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (6-ethyl-1,3-dimethyl-2,4-dioxo- 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide
Intermediate 3 (115 mg, 0.407 mmol) and 4- in the presence of EDCI hydrochloride (156 mg, 0.814 mmol) and DMAP (10 mg, 0.081 mmol) in anhydrous THF: DMF (3: 1, 14 mL). [3-Fluoro-4- (trifluoromethyl) phenyl)]-1,3-thiazol-2-amine (106 mg, 0.407 mmol) is coupled to give 15 mg of product as an off-white solid. The title compound was prepared according to the general procedure (Method B); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.19 (t, J = 7.5 Hz, 3H), 2.79 ( q, J = 7.2 Hz, 2H), 3.18 (s, 3H), 3.45 (s, 3H), 4.07 (s, 2H), 7.80-8 04 (m, 4H), 12.51 (br s, 1H). APCI-MS (m / z) 527.09 (M + H) ^<+> .

Example 32
N- [4- (2,4-difluoro-3-trifluoromethyl) phenyl) -1,3-thiazol-2-yl] -2- (6-ethyl-1,3-dimethyl-2,4-dioxo -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide
Intermediate 3 (200 mg, 0.709 mmol) in the presence of EDCI hydrochloride (271 mg, 1.41 mmol) and DMAP (17 mg, 0.141 mmol) in anhydrous THF: DMF (3: 1, 3.54 mL). Coupling with 4- (2,4-difluoro-3- (trifluoromethyl) phenyl) -1,3-thiazol-2-amine (199 mg, 0.709 mmol) yielding 13 mg as an off-white solid The title compound was prepared according to the general procedure (Method B) by obtaining the product; ¹ H NMR (300 MHz, CDCl ₃ ): δ 1.33 (t, J = 7.2 Hz, 3H), 99 (q, J = 8.1 Hz, 2H), 3.40 (s, 3H), 3.52 (s, 3H), 4.03 (s, 2H), 7.07 d, J = 9.0 Hz, 1H), 7.38 (s, 1H), 8.33 (q, J = 8.4 Hz, 1H), 10.98 (brs, 1H); APCI-MS (M / z) 545.08 (M + H) ^<+> .

Example 33
N- {4- [4- (Difluoromethoxy) -3,5-difluorophenyl] -1,3-thiazol-2-yl} -2- (6-ethyl-1,3-dimethyl-2,4-dioxo -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide
In the presence of EDCI hydrochloride (102 mg, 0.531 mmol), HOBt (18 mg, 0.132 mmol) and DMAP (5.4 mg, 0.044 mmol) in 1,2-dichloroethane (4.5 mL), intermediate 3 (125 mg, 0.443 mmol) and 4- [4- (difluoromethoxy) -3,5-difluorophenyl] -1,3-thiazol-2-amine (123 mg, 0.443 mmol) were coupled to give white The title compound was prepared according to the general procedure (Method A) by obtaining 18 mg of product as a solid of ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.19 (t, J = 7.5 Hz, 3H), 2.78 (q, J = 7.5 Hz, 2H), 3.18 (s, 3H), 3.45 (s, 3H), 4.07 (s, 2H), 7.28 (t, J = 72.3 Hz, 1H), 7.76-7.87 (m, 3H), 12.47 (brs, 1H); ESI- MS (m / z) 464.31 (M-H) ^- .

Example 34
N- {4- [3,5-difluoro-4- (2,2,2-trifluoroethoxy) phenyl] -1,3-thiazol-2-yl} -2- (6-ethyl-1,3- Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide
In the presence of EDCI hydrochloride (122 mg, 0.638 mmol), HOBt (21 mg, 0.159 mmol) and DMAP (6.5 mg, 0.053 mmol) in 1,2-dichloroethane (3 mL), intermediate 3 (150 mg , 0.531 mmol) and 4- [3,5-difluoro-4- (2,2,2-trifluoroethoxy) phenyl] -1,3-thiazol-2-amine (165 mg, 0.531 mmol) The title compound was prepared according to the general procedure (Method A) by ringing to give 60 mg of product as a white solid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.19 (d, J = 7.5 Hz, 3H); 2.78 (q, J = 7.8 Hz, 2H), 3.18 (s, 3H), 3.45 (s) 3H), 4.06 (s, 2H), 4.86 (q, J = 8.7 Hz, 2H), 7.62-7.79 (m, 3H), 12.45 (br s, 1H) APCI-MS (m / z) 575.75 (M + H) ^<+> .

Example 35
N- {4- [3-Fluoro-4- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-6-propyl- 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide
Intermediate 4 (200 mg, 0.674 mmol) in the presence of EDCI hydrochloride (258 mg, 1.349 mmol) and DMAP (16 mg, 0.134 mmol) in anhydrous THF: DMF (3: 1, 3.37 mL). 4- [3-Fluoro-4- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine (176 mg, 0.674 mmol) was coupled to give 12 mg of product as an off-white solid. The title compound was prepared according to the general procedure (Method B) by: ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.94-1.04 (m, 3H), 1.54-1.60 ( m, 2H), 2.70-2.78 (m, 2H), 3.18 (s, 3H), 3.45 (s, 3H), 4.07 (s, 2H) 7.85-8.00 (m, 4H), 12.47 (br s, 1H); ESI-MS (m / z) 540.85 (M + H) +.

Example 36
N- {4- [4-Difluoromethoxy-3,5-difluorophenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-6-propyl-1 , 2,3,4-Tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide
In the presence of EDCI hydrochloride (194 mg, 1.012 mmol) and DMAP (12.3 mg, 0.101 mmol) in a mixture of THF: DMF (3: 1) (2.53 mL), intermediate 4 (150 mg, 0.001). 506 mmol) and 4- [4-difluoromethoxy-3,5-difluorophenyl] -1,3-thiazol-2-amine (140 mg, 0.506 mmol) to produce 12 mg as an off-white solid The title compound was prepared according to the general procedure (Method B) by obtaining ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.00-1.06 (m, 3H), 1.45 1.64 (m, 2H), 2.64-2.84 (m, 2H), 3.17 (s, 3H), 3.45 (s, 3H), 4.06 (S, 2H), 7.28 (t, J = 73.2 Hz, 1H), 7.75-7.87 (m, 3H), 12.46 (brs, 1H). APCI-MS (m / z) 557.57 (M + H) ^<+> .

Example 37
N- {4- [3-Fluoro-4- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (6-isopropyl-1,3-dimethyl-2,4-dioxo- 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide
In the presence of EDCI hydrochloride (85 mg, 0.445 mmol), HOBt (15 mg, 0.111 mmol) and DMAP (4.5 mg, 0.037 mmol) in 1,2-dichloroethane (3.7 mL), intermediate 5 (110 mg, 0.371 mmol) and 4- [3-fluoro-4- (trifluoromethyl) phenyl] -1,3-thiazol-2-amine (97 mg, 0.371 mmol) were coupled to give white The title compound was prepared according to the general procedure (Method A) by obtaining 46 mg of product as a solid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 1.25 (d, J = 6.0 Hz , 6H), 3.18 (s, 3H), 3.38-3.43 (m, 1H), 3.46 (s, 3H), 4.10 (s, 2 ), 7.86-8.05 (m, 4H) , 12.52 (br s, 1H); APCI-MS (m / z) 541.09 (M + H) +.

Example 38
N- [3- (4-Chlorophenyl) isoxazol-5-yl] -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] Pyrimidin-5-yl) acetamide
In the presence of EDCI hydrochloride (90 mg, 0.472 mmol), HOBt (16 mg, 0.118 mmol) and DMAP (5 mg, 0.039 mmol) in 1,2-dichloroethane (4 mL), intermediate 1 (100 mg, 0 393 mmol) and 3- (4-chlorophenyl) isoxazol-5-amine (76 mg, 0.393 mmol) to give 50 mg of product as an off-white solid. The title compound was prepared according to A); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.20 (s, 3H), 3.47 (s, 3H), 4.01 (s, 2H), 6 .67 (s, 1H), 7.07 (s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.85 (d J = 8.4 Hz, 2H), 11.90 (br s, 1H); APCI-MS (m / z) 429.17 (M-H) -.

Example 39
N- [5- (4-Bromophenyl) isoxazol-3-yl] -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] Pyrimidin-5-yl) acetamide
In the presence of EDCI hydrochloride (90 mg, 0.472 mmol), HOBt (16 mg, 0.118 mmol) and DMAP (5 mg, 0.039 mmol) in 1,2-dichloroethane (4 mL), intermediate 1 (100 mg, 0 .393 mmol) and 5- (4-bromophenyl) isoxazol-3-amine (94 mg, 0.393 mmol) to give 45 mg of the product as an off-white solid. The title compound was prepared according to Method A); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.20 (s, 3H), 3.47 (s, 3H), 3.99 (s, 2H), 7.05 (s, 1H), 7.33 (s, 1H), 7.72 (d, J = 8.1 Hz, 2H), 7.81 (d J = 8.4 Hz, 2H), 11.20 (br s, 1H); APCI-MS (m / z) 475.01 (M + H) +.

Example 40
N- [1- (4-Bromophenyl) -1H-pyrazol-3-yl] -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3 -D] pyrimidin-5-yl) acetamide
In the presence of EDCI hydrochloride (90 mg, 0.472 mmol), HOBt (16 mg, 0.118 mmol) and DMAP (5 mg, 0.039 mmol) in 1,2-dichloroethane (6 mL), intermediate 1 (100 mg, 0 .393 mmol) and 1- (4-bromophenyl) -1H-pyrazol-3-amine (93.5 mg, 0.393 mmol) to give 45 mg of product as an off-white solid, The title compound was prepared according to the general procedure (Method A); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.21 (s, 3H), 3.46 (s, 3H), 3.95 (s , 2H), 6.75 (s, 1H), 7.02 (s, 1H), 7.67 (d, J = 8.7 Hz, 2H), 7.74. (D, J = 9.0 Hz, 2H), 8.41 (s, 1H), 10.82 (brs, 1H); APCI-MS (m / z) 475.95 (M + H) ⁺ .

Example 41
N- [3- (4-Chlorophenyl) -1H-pyrazol-5-yl] -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4 d] pyrimidin-5-yl) acetamide
In the presence of EDCI hydrochloride (90 mg, 0.471 mmol), HOBt (16 mg, 0.117 mmol) and DMAP (5 mg, 0.039 mmol) in 1,2-dichloroethane (6 mL), intermediate 1 (100 mg, 0 393 mmol) and 3- (4-chlorophenyl) -1H-pyrazol-5-amine (76 mg, 0.393 mmol) to give 36 mg of product as an off-white solid. The title compound was prepared according to (Method A); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.22 (s, 3H), 3.46 (s, 3H), 3.93 (s, 2H) , 6.86 (s, 1H), 7.01 (s, 1H), 7.50 (d, J = 8.4, 1H), 7.70 (d, = 8.1, 1H), 10.51 ( s, 1H), 12.86 (br s, 1H); ESI-MS (m / z) 428.22 (M-H) -.

Example 42
N- [5- (4-Bromophenyl) -1,3,4-thiadiazol-2-yl] -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide
In the presence of EDCI hydrochloride (90 mg, 0.472 mmol), HOBt (16 mg, 0.118 mmol) and DMAP (5 mg, 0.039 mmol) in 1,2-dichloroethane (4 mL), intermediate 1 (100 mg, 0 393 mmol) and 5- (4-bromophenyl) -1,3,4-thiadiazol-2-amine (101 mg, 0.393 mmol) to give 45 mg of product as an off-white solid. The title compound was prepared according to the general procedure (Method A) by ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.18 (s, 3H), 3.47 (s, 3H), 4.11 (S, 2H), 7.09 (s, 1H), 7.72 (d, J = 8.4 Hz, 2H), 7.87 (d, J = 8 1 Hz, 2H), 12.85 ( br s, 1H); APCI-MS (m / z) 493.93 (M + H) +.

Example 43
N- [4- (4-Bromophenyl) pyrimidin-2-yl] -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] Pyrimidin-5-yl) acetamide
In the presence of EDCI hydrochloride (90 mg, 0.472 mmol), HOBt (16 mg, 0.118 mmol) and DMAP (5 mg, 0.039 mmol) in 1,2-dichloroethane (4 mL), intermediate 1 (100 mg, 0 393 mmol) and 4- (4-bromophenyl) pyrimidin-2-amine (98 mg, 0.393 mmol) to give 28 mg of product as an off-white solid. The title compound was prepared according to A); ¹ H NMR (300 MHz, CF ₃ CO ₂ D) δ 3.57 (s, 3H), 3.77 (s, 3H), 4.45 (s, 2H), 7.18 (s, 1H), 7.80-7.86 (m, 2H), 8.06-8.18 (m, 3H), 8.64-8.7 (M, 1H); APCI- MS (m / z) 485.96 (M) +.

Example 44
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) -N- [4- (4-isobutylphenyl) -1,3-thiazol-2-yl] acetamide
Intermediate 6 (150 mg, 0.531 mmol) and 4- (4-isobutylphenyl) -1 in the presence of sodium hydride (60% dispersion in mineral oil, 43 mg, 1.062 mmol) in anhydrous toluene (6 mL). The title compound was prepared according to the general procedure (Method C) by coupling with 1,3-thiazol-2-amine (148 mg, 0.638 mmol) to give 17 mg of product as an off-white solid; ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 0.90 (d, J = 6.9 Hz, 6H), 1.82-1.92 (m, 1H), 2.48 (d, J = 7.5 Hz, 2H), 3.48 (s, 1H), 3.49, (s, 3H), 4.40 (s, 2H), 6.48 (s, 1H), 7.06 (s , 1H) 7.17 (d, J = 7.8 Hz, 2H), 7.73 (d, J = 7.8 Hz, 2H), 10.57 (br s, 1H); APCI-MS (m / z ) 469.20 (M + H) ⁺ .

Example 45
N- [4- (4-Chlorophenyl) -1,3-thiazol-2-yl] -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3 4-d] pyrimidin-5-yl) acetamide
Intermediate 6 (150 mg, 0.531 mmol) and 4- (4-chlorophenyl) -1, in the presence of sodium hydride (60% dispersion in mineral oil, 43 mg, 1.062 mmol) in anhydrous toluene (6 mL). 3-thiazol-2-amine (133 mg, 0.637 mmol) and was allowed to coupling, by obtaining a product of 90mg as an off-white solid, the title compound was prepared according to the general procedure (method ^{C); 1} H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.38 (s, 3H), 4.55 (s, 2H), 7.01 (s, 1H), 7. 49 (d, J = 8.4, 2H), 7.68 (s, 1H), 7.93 (d, J = 7.8, 2H), 12.59 (brs, 1H); APCI-MS m / z) 447.09 (M + H) +.

Example 46
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) -N- [4- (3-trifluoromethyl) ) Phenyl] -1,3-thiazol-2-yl] acetamide
Intermediate 6 (150 mg, 0.531 mmol) and 4- [3- (trifluoromethyl) in the presence of sodium hydride (60% dispersion in mineral oil, 43 mg, 1.062 mmol) in anhydrous toluene (6 mL). The title compound according to the general procedure (Method C) by coupling with phenyl] -1,3-thiazol-2-amine (155 mg, 0.638 mmol) to give 42 mg of product as an off-white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.39 (s, 3H), 4.55 (s, 2H), 7.02 (s, 1H), 7.65-7.72 (m, 2H), 7.88 (s, 1H), 8.20-8.26 (m, 2H), 12.66 (brs, 1H); APCI -MS (m / z) 481.05 (M + H) ^<+> .

Example 47
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) -N- [4- (4-trifluoromethyl) ) Phenyl] -1,3-thiazol-2-yl] acetamide
Intermediate 6 (150 mg, 0.531 mmol) and 4- [4- (trifluoromethyl) in the presence of sodium hydride (60% dispersion in mineral oil, 43 mg, 1.062 mmol) in anhydrous toluene (6 mL). The title compound according to the general procedure (Method C) by coupling with phenyl] -1,3-thiazol-2-amine (155 mg, 0.638 mmol) to give 23 mg of product as an off-white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.20 (s, 3H), 3.40 (s, 3H), 4.56 (s, 2H), 7.03 (s, 1H), 7.81 (d, J = 8.1, 2H), 7.86 (s, 1H), 8.12 (d, J = 8.4, 2H), 12.66 (br s, 1H) ); APCI-MS (m / z) 481.11 (M + H) ^<+> .

Example 48
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) -N- {4- [3- (trifluoro Methoxy) phenyl] -1,3-thiazol-2-yl} acetamide
Intermediate 6 (150 mg, 0.531 mmol) and 4- [3- (trifluoromethoxy) in the presence of sodium hydride (60% dispersion in mineral oil, 43 mg, 1.062 mmol) in anhydrous toluene (6 mL). The title compound according to the general procedure (Method C) by coupling with phenyl] -1,3-thiazol-2-amine (165 mg, 0.638 mmol) to give 240 mg of product as an off-white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.40 (s, 3H), 4.55 (s, 2H), 7.03 (s, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.58 (t, J = 7.8 Hz, 1H), 7.81 (s, 1H), 7.87 (s, 1 H), 7.95 (d, J = 8.4 Hz, 1H), 12.63 (brs, 1H); APCI-MS (m / z) 497.09 (M + H) ⁺ .

Example 49
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) -N- {4- [4-fluoro-3 -(Trifluoromethyl) phenyl] -1,3-thiazol-2-yl} acetamide
In the presence of sodium hydride (60% dispersion in mineral oil, 43 mg, 1.062 mmol) in anhydrous toluene (6 mL), intermediate 6 (150 mg, 0.531 mmol) and 4- [4-fluoro-3- ( Trifluoromethyl) phenyl] -1,3-thiazol-2-amine (167 mg, 0.638 mmol) was coupled to give 90 mg of product as an off-white solid by the general procedure (Method C ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.39 (s, 3H), 4.55 (s, 2H), 7. 03 (s, 1H), 7.61 (t, J = 9.0 Hz, 1H), 7.86 (s, 1H), 8.24-8.30 (m, 2H), 12.66 (b s, 1H); APCI-MS (m / z) 499.00 (M + H) +.

Example 50
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) -N- {4- [3-fluoro-4 -(Trifluoromethyl) phenyl] -1,3-thiazol-2-yl} acetamide
In the presence of sodium hydride (60% dispersion in mineral oil, 43 mg, 1.062 mmol) in anhydrous toluene (6 mL), intermediate 6 (150 mg, 0.531 mmol) and 4- [3-fluoro-4- ( Coupling with (trifluoromethyl) phenyl] -1,3-thiazol-2-amine (167 mg, 0.638 mmol) to give 68 mg of product as an off-white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.39 (s, 3H), 4.56 (s, 2H), 7. 03 (s, 1H), 7.83-7.97 (m, 3H), 7.99 (s, 1H), 12.68 (brs, 1H); APCI-MS (m / z) 4 9.09 (M + ^H) +.

Example 51
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) -N- {4- [2-fluoro-4 -(Trifluoromethyl) phenyl] -1,3-thiazol-2-yl} acetamide
In the presence of sodium hydride (60% dispersion in mineral oil, 25 mg, 0.638 mmol) in anhydrous toluene (4 mL), intermediate 6 (90 mg, 0.319 mmol) and 4- [2-fluoro-4- ( General procedure (Method C) by coupling trifluoromethyl) phenyl] -1,3-thiazol-2-amine (100 mg, 0.382 mmol) to give 150 mg of product as a white solid. The title compound was prepared according to ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.20 (s, 3H), 3.39 (s, 3H), 4.55 (s, 2H), 7.02 (S, 1H), 7.68-7.82 (m, 3H), 8.27 (t, J = 7.8 Hz, 1H), 12.46 (br s, 1H); APCI-MS ( ^{/ Z) 499.05 (M + H} ) +.

Example 52
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) -N- {4- [3-fluoro-4 -(Trifluoromethoxy) phenyl] -1,3-thiazol-2-yl} acetamide
In the presence of sodium hydride (60% dispersion in mineral oil, 43 mg, 1.062 mmol) in anhydrous toluene (6 mL), intermediate 6 (150 mg, 0.531 mmol) and 4- [3-fluoro-4- ( Coupling with (trifluoromethoxy) phenyl] -1,3-thiazol-2-amine (177 mg, 0.638 mmol) to give 35 mg of product as an off-white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.39 (s, 3H), 4.56 (s, 2H), 7. 03 (s, 1H), 7.67 (t, J = 7.8 Hz, 1H), 7.82-7.89 (m, 2H), 7.98 (d, J = 9.0 Hz, 1H) ), 12.65 (br s, 1H); APCI-MS (m / z) 515.18 (M + H) ⁺ .

Example 53
N- [4- (3,4-Dichlorophenyl) -1,3-thiazol-2-yl] -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [ 3,4-d] pyrimidin-5-yl) acetamide
Intermediate 6 (150 mg, 0.531 mmol) and 4- (3,4-dichlorophenyl)-in the presence of sodium hydride (60% dispersion in mineral oil, 43 mg, 1.062 mmol) in anhydrous toluene (6 mL). The title compound was prepared according to the general procedure (Method C) by coupling with 1,3-thiazol-2-amine (156 mg, 0.638 mmol) to give 15 mg of product as an off-white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.39 (s, 3H), 4.55 (s, 2H), 7.03 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.84 (s, 1H), 7.89 (d, J = 6.6 Hz, 1H), 12.65 (br s, 1H) ; PCI-MS (m / z) 481.07 (M + H) +.

Example 54
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) -N- {4- [3-fluoro-5 -(Trifluoromethyl) phenyl] -1,3-thiazol-2-yl} acetamide
In the presence of sodium hydride (60% dispersion in mineral oil, 43 mg, 1.062 mmol) in anhydrous toluene (6 mL), intermediate 6 (150 mg, 0.531 mmol) and 4- [3-fluoro-5- ( General procedure (method) by coupling with (trifluoromethyl) phenyl] -1,3-thiazol-2-amine (167.8 mg, 0.638 mmol) to give 13 mg of product as a white solid. The title compound was prepared according to C); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.39 (s, 3H), 4.56 (s, 2H), 7 .03 (s, 1H), 7.65 (d, J = 8.4, 1H), 8.01 (s, 1H), 8.06 (d, J = 10.2 Hz, 1H), 8. 13 (s 1H), 12.68 (br s, 1H); APCI-MS (m / z) 499.07 (M + H) +.

Example 55
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) -N- {4- [4-fluoro-3 -(Trifluoromethoxy) phenyl] -1,3-thiazol-2-yl} acetamide
In the presence of sodium hydride (60% dispersion in mineral oil, 36 mg, 0.744 mmol) in anhydrous toluene (6 mL), intermediate 6 (150 mg, 0.531 mmol) and 4- [4-fluoro-3- ( Coupling with (trifluoromethoxy) phenyl] -1,3-thiazol-2-amine (177 mg, 0.638 mmol) to give 55 mg of product as an off-white solid. ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.39 (s, 3H), 4.55 (s, 2H), 7. 03 (s, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.80 (s, 1H), 8.00-8.05 (m, 2H), 12.63 ( r s, 1H); APCI- MS (m / z) 513.12 (M-H) -.

Example 56
N- {4- [2,3-difluoro-4- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) acetamide
Intermediate 6 (150 mg, 0.531 mmol) and 4- [2,3-difluoro-4 in the presence of sodium hydride (60% dispersion in mineral oil, 43 mg, 1.062 mmol) in anhydrous toluene (6 mL). Coupling with-(trifluoromethyl) phenyl] -1,3-thiazol-2-amine (179 mg, 0.638 mmol) to give 42 mg of product as an off-white solid. The title compound was prepared according to Method C); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.40 (s, 3H), 4.57 (s, 2H), 7.03 (s, 1H), 7.74 (t, J = 7.5, 1H), 7.81 (s, 1H), 8.02 (d, J = 6.6, 1H), 12. 73 (Br s, 1H); APCI-MS (m / z) 517.04 (M + H) ^<+> .

Example 57
N- {4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) acetamide
Intermediate 6 (150 mg, 0.531 mmol) and 4- [2,4-difluoro-3 in the presence of sodium hydride (60% dispersion in mineral oil, 43 mg, 1.062 mmol) in anhydrous toluene (6 mL). Coupling with-(trifluoromethyl) phenyl] -1,3-thiazol-2-amine (179 mg, 0.638 mmol) to give 42 mg of product as an off-white solid. The title compound was prepared according to Method C); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.39 (s, 3H), 4.56 (s, 2H), 7.03 (s, 1H), 7.51 (t, J = 9.0 Hz, 1H), 7.64 (s, 1H), 8.34 (q, J = 6.9 Hz, 1H), 2.67 (br s, 1H); APCI-MS (m / z) 517.39 (M + H) +.

Example 58
N- {4- [3,5-difluoro-4- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) acetamide
Intermediate 6 (150 mg, 0.531 mmol) and 4- [3,5-difluoro-4 in the presence of sodium hydride (60% dispersion in mineral oil, 43 mg, 1.062 mmol) in anhydrous toluene (6 mL). Coupling with-(trifluoromethyl) phenyl] -1,3-thiazol-2-amine (179 mg, 0.638 mmol) to give 40 mg of product as an off-white solid. The title compound was prepared according to Method C); ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.39 (s, 3H), 4.56 (s, 2H), 7.03 (s, 1H), 7.83 (s, 1H), 7.87 (s, 1H), 8.09 (s, 1H), 12.70 (brs, 1H); APCI -MS (m / z) 517.04 (M + H) ^<+> .

Example 59
N- {4- [4- (Difluoromethoxy) -3,5-difluorophenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1,2 , 3,4-Tetrahydrothieno [3,4-d] pyrimidin-5-yl) acetamide
Intermediate 6 (150 mg, 0.531 mmol) and 4- [4- (difluoromethoxy)-in the presence of sodium hydride (60% dispersion in mineral oil, 43 mg, 1.062 mmol) in anhydrous toluene (6 mL). Coupling with 3,5-difluorophenyl] -1,3-thiazol-2-amine (176 mg, 0.638 mmol) to give 50 mg of product as a brown solid, the general procedure (Method C ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.19 (s, 3H), 3.39 (s, 3H), 4.56 (s, 2H), 7. 03 (s, 1H), 7.27 (t, J = 73.8, 1H), 7.77 (s, 1H), 7.80 (s, 1H), 7.88 (s, 1H), 12 . 4 (br s, 1H); APCI-MS (m / z) 481.05 (M + H) +.

Example 60
N- {4- [3,5-difluoro-4- (2,2,2 - trifluoro-ethoxy) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2 , 4-Dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) acetamide
Intermediate 6 (150 mg, 0.531 mmol) and 4- [3,5-difluoro-4 in the presence of sodium hydride (60% dispersion in mineral oil, 43 mg, 1.062 mmol) in anhydrous toluene (6 mL). Coupling with-(2,2,2-trifluoroethoxy) phenyl] -1,3-thiazol-2-amine (197 mg, 0.638 mmol) to give 45 mg of product as an off-white solid. The title compound was prepared according to the general procedure (Method C) by ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 3.22 (s, 3H), 3.45 (s, 3H), 4.61. (S, 2H), 4.91 (q, J = 8.7 Hz, 2H), 7.08 (s, 1H), 7.76 (d, J = 9.9 Hz, 2H), 7.86 ( , 1H), 12.66 (br s , 1H); APCI-MS (m / z) 547.17 (M + H) +.

Pharmacological activity (a) Toeth, A .; et al. , Life Sciences, 2003, 73, 487-498. (B) McNamara C, R .; et al. , Proc. Natl. Acad. Sci. U. S. A. , 2007, 104, 13525-13530, examples of the invention are screened for TRPA1 activity according to a modified procedure. Compound screening can also be performed by other methods and procedures known to those skilled in the art.

Screening for TRPA1 antagonists using a ⁴⁵ calcium uptake assay TRPA1 receptor activation inhibition was measured as inhibition of radioactive calcium uptake induced by allylisothiocyanate (AITC).
Test compounds were dissolved in 100% DMSO to prepare a 10 mM stock solution and then diluted to the desired concentration using normal medium containing 0.1% BSA and 1.8 mM CaCl ₂ . The final concentration of DMSO in the reaction was 0.5% (v / v). CHO cells expressing human TRPA1 were grown in F-12 DMEM medium containing 10% FBS, 1% penicillin-streptomycin solution, 400 μg / mL G-418. CHO cells expressing rat TRPA1 were grown in F-12 DMEM medium containing 10% FBS, 1% penicillin-streptomycin solution, 400 μg / mL Zeocin. The cells were seeded in 96-well plates 24 hours prior to the assay so that there were approximately 50,000 cells per well on the day of the experiment. The cells were treated with the test compound for 10 minutes and then added for 3 minutes at a final concentration of 30 μM (for human TRPA1) and / or 10 μM (for rat TRPA1) and 5 μCi / mL ⁴⁵ Ca ²⁺ . The cells were washed and lysed using a buffer containing 1% Triton X-100, 0.1% deoxycholate, and 0.1% SDS. After adding the liquid scintillator, the radioactivity of the lysate was measured with a Packard TopCount. (Toth et al, Life Sciences (2003) 73, 487-498; McNamara CR et al, Proceedings of the National Academy of Sciences, (2007) 104, 13525-13530).
Concentration response curves were plotted as a percentage of the maximum response obtained in the absence of test antagonist. IC ₅₀ values can be calculated from concentration response curves by non-linear regression analysis using GraphPad PRISM software.

The prepared compounds were tested using the above assay procedure, and the results obtained in the case of humans are shown in Table 2, and the results obtained in the case of rats are shown in Table 3, respectively. Along with the IC ₅₀ (nM) details for selected examples, the percent inhibition at 1.0 μM and 10.0 μM concentrations is also shown in the table. The IC ₅₀ (nM) values of the compounds are listed in Tables 2 and 3, where “A” indicates that the IC ₅₀ value is less than 50 nM, and “B” indicates that the IC ₅₀ value is from 50.01 nM to 500.0 nM.

Claims (31)

Formula (I):
Or a pharmaceutically acceptable salt thereof (wherein
R ¹ and R ² may be the same or different and are independently hydrogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, (CR ^x R ^y ) _n OR ^x , COR ^x , COOR ^x , CONR ^x R ^y , (CH ₂ ) _n NR ^x R ^y , (CH ₂ ) _n CHR ^x R ^y , and (CH ₂ ) _n NHCOR ^x ;
R ³ is selected from hydrogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, and cycloalkenyl;
L _{^{is, - (CR x R y)}} n -, - O- (CR x R y) n -, - C (O) -, - NR x -, - S (O) m NR x -, - NR x _{^{(CR x R y) n -}} , and _{^{-S (O) m NR x (}} CR x R y) is a linker selected from _n;
Z ₁ and Z ₂ are independently sulfur or CR ^a ,
Provided that either Z ₁ or Z ₂ is always sulfur and the other is CR ^a ;
R ^a is hydrogen, cyano, halogen, substituted or unsubstituted alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, OR ^x , (CR ^x R ^y ) _n OR ^x , COR ^x , COOR ^x , CONR ^{x _{R y, S (O) m}} NR x R y, NR x R y, NR x (CR x R y) n OR x, (CH 2) n NR x R y, (CH 2) n CHR x R y, _{^{NR x (CR x R y)}} n CONR x R y, (CH 2) n NHCOR x, (CH 2) n NH (CH 2) n SO 2 R x, (CH 2) n NHSO 2 R x, SR x , And OR ^x ;
U is substituted or unsubstituted aryl; thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyrazole, imidazole, furan, thiophene, pyrrole, 1,2,3-triazole, and 1,2,4- A substituted or unsubstituted 5-membered heterocyclic ring selected from the group consisting of triazoles; or selected from a substituted or unsubstituted 6-membered heterocyclic ring selected from the group consisting of pyrimidines, pyridines, and pyridazines;
V is hydrogen, cyano, nitro, —NR ^x R ^y , halogen, hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, haloalkyl, haloalkoxy, cycloalkylalkoxy, aryl, Arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocycle, heterocyclylalkyl, —C (O) OR ^x , —OR ^x , —C (O) NR ^x R ^y , —C (O) R ^x , and — Is selected from SO ₂ NR ^x R ^y ;
Alternatively, U and V together form an optionally substituted 3-7 membered saturated or unsaturated ring optionally containing one or more heteroatoms selected from O, S, and N. May be:
At each occurrence, R ^x and R ^y are independently hydrogen, hydroxyl, halogen, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, Selected from heteroarylalkyl, heterocycle, and heterocyclylalkyl;
At each occurrence, “m” and “n” are independently selected from 0 to 2). The compound according to claim 1, wherein L is CH ₂ . The compound according to claim ^1, wherein R ¹ and R ² are (C ₁ -C ₄ ) alkyl. _(C 1 -C ₄₎ alkyl, A compound according to claim 3 is methyl. R < ³ > is hydrogen, The compound in any one of Claims 1-4.   The compound according to any one of claims 1 to 5, wherein U is thiazole, imidazole, isoxazole, pyrazole, thiadiazole, or pyrimidine.   The compound according to any one of claims 1 to 6, wherein V is substituted or unsubstituted aryl.   8. A compound according to claim 7, wherein aryl is phenyl. Formula (Ia):
Or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ^a , U, and V are as defined in claim 1. .
The compound according to claim 9, wherein R ¹ and R ² are (C ₁ -C ₄ ) alkyl. _(C 1 -C ₄₎ alkyl, A compound according to claim 10 which is methyl. The compound according to any one of claims 9 to 11, wherein R ^a is hydrogen or (C ₁ -C ₄ ) alkyl.   The compound according to any one of claims 9 to 12, wherein U is thiazole, imidazole, isoxazole, pyrazole, thiadiazole, or pyrimidine.   The compound according to any one of claims 9 to 13, wherein V is substituted or unsubstituted aryl.   15. A compound according to claim 14, wherein aryl is phenyl. Formula (Ic):
Or a pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , and R ^a may be the same or different and are independent of each other. Hydrogen or (C ₁ -C ₄ ) alkyl;
R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , and R ⁹ may be the same or different and are each independently hydrogen, halogen, cyano, hydroxy, nitro, amino, substituted Or from the group consisting of unsubstituted alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkylalkoxy, aryl, arylalkyl, biaryl, heteroaryl, heteroarylalkyl, heterocycle, and heterocyclylalkyl Selected). The compound according to claim 16, wherein R ¹ and R ² are (C ₁ -C ₄ ) alkyl. _(C 1 -C ₄₎ alkyl, A compound according to claim 17 which is methyl. R ⁴ and R ⁵ are independently hydrogen, fluoro, trifluoromethyl, and A compound according to any one of claims 16-18 which is selected from the group consisting trifluoromethoxy. R ⁶ and R ⁷ are independently hydrogen, fluoro, trifluoromethyl, and A compound according to any one of claims 16 to 19 which is selected from the group consisting trifluoromethoxy. A compound according to any one of claims 16 to 20 R ⁸ and ^{R 9} are hydrogen. A compound selected from:
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) -N- [4- (trifluoromethyl)- 1,3-thiazol-2-yl] acetamide;
N- [4- (4-Chlorophenyl) -1,3-thiazol-2-yl] -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2, 3-d] pyrimidin-5-yl) acetamide;
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) -N- {4- [3- (trifluoro Methoxy) phenyl] -1,3-thiazol-2-yl} acetamide;
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) -N- [4- (4-isobutylphenyl) -1,3-thiazol-2-yl] acetamide;
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) -N- {4- [4-fluoro-3 -(Trifluoromethyl) phenyl] -1,3-thiazol-2-yl} acetamide;
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) -N- {4- [4-fluoro-3 -(Trifluoromethyl) phenyl] -1,3-thiazol-2-yl} acetamide;
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) -N- {4- [2-fluoro-4 -(Trifluoromethyl) phenyl] -1,3-thiazol-2-yl} acetamide;
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) -N- {4- [3-fluoro-5 -(Trifluoromethyl) phenyl] -1,3-thiazol-2-yl} acetamide;
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) -N- {4- [2-fluoro-3 -(Trifluoromethyl) phenyl] -1,3-thiazol-2-yl} acetamide;
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) -N- {4- [4-fluoro-3 -(Trifluoromethoxy) phenyl] -1,3-thiazol-2-yl} acetamide;
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) -N- {4- [3-fluoro-4 -(Trifluoromethoxy) phenyl] -1,3-thiazol-2-yl} acetamide;
N- [4- (3,4-Dichlorophenyl) -1,3-thiazol-2-yl] -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [ 2,3-d] pyrimidin-5-yl) acetamide;
N- {4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide;
[N- {4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1 , 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamido] sodium;
N- {4- [2,3-difluoro-4- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide;
N- {4- [3,5-difluoro-4- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide;
N- [4- (4-tert-butylphenyl) -1,3-thiazol-2-yl] -2- (1,3,6-trimethyl-2,4-dioxo-1,2,3,4- Tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide;
N- {4- [3- (trifluoromethoxy) phenyl] -1,3-thiazol-2-yl} -2- (1,3,6-trimethyl-2,4-dioxo-1,2,3 4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide;
N- [4- (4-Chlorophenyl) -1,3-thiazol-2-yl] -2- (1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [ 2,3-d] pyrimidin-5-yl) acetamide;
N- [4- (3,4-Dichlorophenyl) -1,3-thiazol-2-yl] -2- (1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydro Thieno [2,3-d] pyrimidin-5-yl) acetamide;
N- [4- (2,3-difluorophenyl) -1,3-thiazol-2-yl] -2- (1,3,6-trimethyl-2,4-dioxo-1,2,3,4- Tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide;
N- [4- (2,4-difluorophenyl) -1,3-thiazol-2-yl] -2- (1,3,6-trimethyl-2,4-dioxo-1,2,3,4- Tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide;
N- {4- [4-Fluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3,6-trimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide;
N- {4- [3-Fluoro-4- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3,6-trimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide;
N- {4- [4-Fluoro-3- (trifluoromethoxy) phenyl] -1,3-thiazol-2-yl} -2- (1,3,6-trimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide;
N- {4- [3-Fluoro-4- (trifluoromethoxy) phenyl] -1,3-thiazol-2-yl} -2- (1,3,6-trimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide;
N- {4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3,6-trimethyl-2,4-dioxo- 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide;
N- [4- (3-trifluoromethoxyphenyl) -1H-imidazol-2-yl] -2- (1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide;
N- {4- [3-Fluoro-4- (trifluoromethyl) phenyl] -1H-imidazol-2-yl} -2- (1,3,6-trimethyl-2,4-dioxo-1,2, 3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide;
N- [4- (4-Cyanophenyl) -1,3-thiazol-2-yl] -2- (6-ethyl-1,3-dimethyl-2,4-dioxo-1,2,3,4- Tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide;
N- {4- [3-Fluoro-4- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (6-ethyl-1,3-dimethyl-2,4-dioxo- 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide;
N- [4- (2,4-difluoro-3-trifluoromethyl) phenyl) -1,3-thiazol-2-yl] -2- (6-ethyl-1,3-dimethyl-2,4-dioxo -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide;
N- {4- [4- (Difluoromethoxy) -3,5-difluorophenyl] -1,3-thiazol-2-yl} -2- (6-ethyl-1,3-dimethyl-2,4-dioxo -1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide;
N- {4- [3,5-difluoro-4- (2,2,2-trifluoroethoxy) phenyl] -1,3-thiazol-2-yl} -2- (6-ethyl-1,3- Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide;
N- {4- [3-Fluoro-4- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-6-propyl- 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide;
N- {4- [4-Difluoromethoxy-3,5-difluorophenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-6-propyl-1 , 2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide;
N- {4- [3-Fluoro-4- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (6-isopropyl-1,3-dimethyl-2,4-dioxo- 1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide;
N- [3- (4-Chlorophenyl) isoxazol-5-yl] -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] Pyrimidin-5-yl) acetamide;
N- [5- (4-Bromophenyl) isoxazol-3-yl] -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d ] Pyrimidin-5-yl) acetamide;
N- [1- (4-Bromophenyl) -1H-pyrazol-3-yl] -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3 -D] pyrimidin-5-yl) acetamide;
N- [3- (4-Chlorophenyl) -1H-pyrazol-5-yl] -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4 d] pyrimidin-5-yl) acetamide;
N- [5- (4-Bromophenyl) -1,3,4-thiadiazol-2-yl] -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] pyrimidin-5-yl) acetamide;
N- [4- (4-Bromophenyl) pyrimidin-2-yl] -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [2,3-d] Pyrimidin-5-yl) acetamide;
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) -N- [4- (4-isobutylphenyl) -1,3-thiazol-2-yl] acetamide;
N- [4- (4-Chlorophenyl) -1,3-thiazol-2-yl] -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3 4-d] pyrimidin-5-yl) acetamide;
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) -N- [4- (3-trifluoromethyl) ) Phenyl] -1,3-thiazol-2-yl] acetamide;
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) -N- [4- (4-trifluoromethyl) ) Phenyl] -1,3-thiazol-2-yl] acetamide;
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) -N- {4- [3- (trifluoro Methoxy) phenyl] -1,3-thiazol-2-yl} acetamide;
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) -N- {4- [4-fluoro-3 -(Trifluoromethyl) phenyl] -1,3-thiazol-2-yl} acetamide;
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) -N- {4- [3-fluoro-4 -(Trifluoromethyl) phenyl] -1,3-thiazol-2-yl} acetamide;
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) -N- {4- [2-fluoro-4 -(Trifluoromethyl) phenyl] -1,3-thiazol-2-yl} acetamide;
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) -N- {4- [3-fluoro-4 -(Trifluoromethoxy) phenyl] -1,3-thiazol-2-yl} acetamide;
N- [4- (3,4-Dichlorophenyl) -1,3-thiazol-2-yl] -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [ 3,4-d] pyrimidin-5-yl) acetamide;
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) -N- {4- [3-fluoro-5 -(Trifluoromethyl) phenyl] -1,3-thiazol-2-yl} acetamide;
2- (1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) -N- {4- [4-fluoro-3 -(Trifluoromethoxy) phenyl] -1,3-thiazol-2-yl} acetamide;
N- {4- [2,3-difluoro-4- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) acetamide;
N- {4- [2,4-difluoro-3- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) acetamide;
N- {4- [3,5-difluoro-4- (trifluoromethyl) phenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1, 2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) acetamide;
N- {4- [4- (Difluoromethoxy) -3,5-difluorophenyl] -1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1,2 , 3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) acetamide; and N- {4- [3,5-difluoro-4- (2,2,2-difluoroethoxy) phenyl]- 1,3-thiazol-2-yl} -2- (1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydrothieno [3,4-d] pyrimidin-5-yl) acetamide ;
Or a pharmaceutically acceptable salt thereof. The following formula:
Or a pharmaceutically acceptable salt thereof. The following formula:
Or a pharmaceutically acceptable salt thereof. The following formula:
Or a pharmaceutically acceptable salt thereof. The following formula:
Or a pharmaceutically acceptable salt thereof. The following formula:
Or a pharmaceutically acceptable salt thereof.   28. A pharmaceutical composition comprising one or more compounds selected from the compounds of any one of claims 1 to 27 and one or more pharmaceutically acceptable excipients, carriers, diluents, or mixtures thereof. . Prevention of a disease or condition associated with TRPA1 function in a subject, a composition for improving or treating, seen containing a compound according to any one of claims 1 to 27,
The disease or symptom related to the TRPA1 function is pain, chronic pain, complex local pain syndrome, neuropathic pain, postoperative pain, rheumatoid arthritis pain, osteoarthritis pain, back pain, visceral pain, cancer pain, Hyperalgesia, neuralgia, migraine, neuropathy, diabetic neuropathy, sciatica, HIV-related neuropathy, postherpetic neuralgia, fibromyalgia, nerve injury, ischemia, neurodegeneration, stroke, poststroke pain, multiple sclerosis, Respiratory disease, asthma, cough, COPD, inflammatory disorder, esophagitis, gastroesophageal reflux disease (GERD), irritable bowel syndrome, inflammatory bowel disease, pelvic hypersensitivity, urinary incontinence, cystitis, burns, psoriasis, A composition selected from eczema, vomiting, gastroduodenal ulcer, and pruritus . A composition for the treatment of pain in a subject comprising a compound according to any of claims 1 to 27, wherein the compound is contained in a therapeutically effective amount. The composition according to claim 30, wherein the pain is chronic pain, neuropathic pain, rheumatic pain, or osteoarthritic pain.